AU2019205881A1 - Novel metal complex, method for producing same, and method for producing gamma-lactam compound using same - Google Patents

Novel metal complex, method for producing same, and method for producing gamma-lactam compound using same Download PDF

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AU2019205881A1
AU2019205881A1 AU2019205881A AU2019205881A AU2019205881A1 AU 2019205881 A1 AU2019205881 A1 AU 2019205881A1 AU 2019205881 A AU2019205881 A AU 2019205881A AU 2019205881 A AU2019205881 A AU 2019205881A AU 2019205881 A1 AU2019205881 A1 AU 2019205881A1
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alkyl
chemical formula
aryl
nmr
pct2018
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AU2019205881B2 (en
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Sukbok Chang
Seung Youn HONG
Yeongyu HWANG
Yeong Bum Kim
Yoon Su Park
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Korea Advanced Institute of Science and Technology KAIST
Institute for Basic Science
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Korea Advanced Institute of Science and Technology KAIST
Institute for Basic Science
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Abstract

The present invention relates to a novel metal complex, a method for producing same, and a method for producing a gamma-lactam compound using same, and the metal complex according to the present invention is used as a catalyst for producing a gamma-lactam compound and can efficiently produce a gamma-lactam compound with an excellent yield and excellent selectivity.

Description

PLUS International IP Law Firm Our ref. PCT2018-151
[DESCRIPTION]
[Invention Title] NOVEL METAL COMPLEX, METHOD FOR
PRODUCING SAME, AND METHOD FOR PRODUCING GAMMA-LACTAM COMPOUND US ING SAME
[Technical Field]
[1] The present invention relates to a novel metal
complex, a method of preparing the same, and a method of
preparing a gamma-lactam compound using the same, and more
particularly, to a novel metal complex allowing a gamma
lactam compound to be prepared from a dioxazol-one compound
with excellent selectivity and yield, a method of preparing
the same, and a method of preparing a gamma-lactam compound
using the same.
[Background Art]
[2] The most preferred method of purifying hydrocarbon
with low added value which is supplied in large quantities
in petroleum or a renewable biomass source into a chemical
material with high added value is a reaction of oxidizing a
C-H bond using a catalyst.
[3] Therefore, the reaction of oxidizing a C-H bond using
a catalyst is regarded as being one of the most important
reactions in chemistry, and a nitration reaction of an
PLUS International IP Law Firm Our ref. PCT2018-151
aliphatic compound having a C-H compound using a catalyst
is a very important reaction which is most commonly used in
various organic synthesis, medicines, and material
chemistry.
[4] An effective and general method for performing a C-N
coupling reaction is to convert a nucleophilic amino
functional group into an electrophilic nitrene having a
much stronger reactivity in a C-H amidation reaction using
a metal catalyst.
[5] This reaction is very efficient and the related
reactions have been studied by many researchers for a long
time.
[6] As an example, it is known by Breslow et al. that in
the synthesis of oxathiazolidine catalyzed by Fe(III) or
Rh(II), ROSO 2N=IR' (iminoiodinanes) which is a reactive
peroxide may serve as a sulfonylnitrene precursor, and
thereafter, various methods related thereto have been
studied.
[7] However, C-H amidation has an unsolved problem for
being applied to preparation of cyclic amides such as
lactam which is very useful for a raw material and an
intermediate in organic synthesis and a medicinal use, and
the route thereof is also unclear.
[8] The simplest precursor and the most important
intermediate which may directly produce a cyclic amide
PLUS International IP Law Firm Our ref. PCT2018-151
compound is known as carbonylnitrene produced in an in-situ
reaction.
[9] Therefore, in principle, it is considered that in a
catalytic reaction using a metal, the reaction proceeds
through a main metal-nitrene intermediate and then a C-H
bond is inserted to produce an aziheterocyclic compound
corresponding thereto.
[10] However, the main reason for not synthesizing a
lactam compound by the C-H amidation reaction is that a
metal-carbonylnitrene intermediate which is regarded as an
intermediate is unstable and easily produce isocyanate by
Curtius type rearrangement.
[11] This instability is also accounted for as acyl azide
as a synthesis precursor under photolysis, pyrolysis, and
transition metal catalyst conditions.
[12] Accordingly, acyl azide is inappropriate as an amide
source of a C-H amidation reaction and a specific amide
source is needed, and furthermore, a study on a catalyst
for preparing a lactam compound with excellent selectivity
and yield is also needed.
[Disclosure]
[Technical Problem]
[13] While trying to solve the problem described above,
the present inventor found that a gamma-lactam compound may
PLUS International IP Law Firm Our ref. PCT2018-151
be prepared with excellent selectivity and yield by a novel
metal complex having a specific functional group, thereby
completing the present invention.
[14] Therefore, an object of the present invention is to
provide a novel metal complex, a method of preparing the
same, and a method of preparing a gamma-lactam compound
using the same.
[15] Another object of the present invention is to provide
a lactam compound prepared by the method of preparing a
gamma-lactam compound.
[Technical Solution]
[16] In one general aspect, a novel metal complex used as
a catalyst for preparing a gamma-lactam compound is
provided, which is represented by the following Chemical
formula 1:
[17] [Chemical Formula 1]
L
A-R7
[18] (Re)n
[19] wherein
[20] M is iridium, rhodium, ruthenium, or cobalt;
PLUS International IP Law Firm Our ref. PCT2018-151
R3
R4 R2
[21] L is -- or
[22] X is a halogen;
[23] Ri to R 5 are independently of one another hydrogen or
(C1-C20)alkyl; and
[24] R6 is a halogen, (C1-C20)alkyl, halo(C1-C20)alkyl,
(C1-C20)alkoxy, (C6-C20)aryl, or (C3-C20)heteroaryl;
[25] A is -CO- or -SO 2 -;
[26] R7 is (C1-C20)alkyl, (C1-C20)alkoxy, (C6-C20)aryl,
(C1-C20)alkyl(C6-C20)aryl, or -NR 11 R 12 ;
[27] R 11 and R 1 2 are independently of each other hydrogen
or (C1-C20)alkyl; and
[28] n is an integer of 0 to 6.
[29] Preferably, in Chemical Formula 1 according to an
exemplary embodiment of the present invention, L may be
R3
R4 R2
R5 ; X may be Cl or Br; Ri to R5 may be
independently of one another (C1-C20)alkyl; R6 may be
halo(C1-C20)alkyl or (C1-C20)alkoxy; and n may be an
integer of 0 to 6.
[30] Preferably, Chemical Formula 1 according to an
PLUS International IP Law Firm Our ref. PCT2018-151
exemplary embodiment of the present invention may be
represented by the following Chemical Formula 2:
[31] [Chemical Formula 2]
CH 3 H 3C OH 3
H3C CH 3
A-Ry
[32] (RO)
[33] wherein
[34] X is a halogen;
[35] R 6 is halo(Cl-C20)alkyl or (C1-C20)alkoxy;
[36] A is -CO- or -SO 2 -;
[37] R7 is (C1-C20)alkyl, (C1-C20)alkoxy, (C6-C20)aryl,
(C1-C20)alkyl(C6-C20)aryl, or -NR 1 1 R 12 ;
[38] R11 and R12 are independently of each other hydrogen
or (C1-C20)alkyl; and
[39] n is an integer of 0 or 1.
[40] Preferably, in Chemical Formula 2 according to an
exemplary embodiment of the present invention, A may be
CO-; R6 and R7 may be independently of each other (Cl
C20)alkoxy; and n may be an integer of 1.
[41] The metal complex of Chemical Formula 1 according to
an exemplary embodiment of the present invention may be
PLUS International IP Law Firm Our ref. PCT2018-151
used as a catalyst for preparing a gamma-lactam compound
from a dioxazol-one compound.
[42] In another general aspect, a method of preparing a
metal complex represented by the following Chemical Formula
1 includes: reacting a metal precursor compound of the
following Chemical Formula 3A and a quinoline-based
compound of the following Chemical Formula 3B in the
presence of a base to prepare the metal complex of the
following Chemical Formula 1:
[43] [Chemical Formula 1]
L
A-R7
[44] (Re)n
[45] [Chemical Formula 3A]
L X-M-X X M-X
[46] L
[47] [Chemical Formula 3B]
(R), N HN
[48] 'A-R7
[49] wherein
PLUS International IP Law Firm Our ref. PCT2018-151
[50] M is iridium, rhodium, ruthenium, or cobalt;
R3
R4R RR2
[51] L is R- or
[52] X is independently of each other a halogen;
[53] Ri to R 5 are independently of one another hydrogen or
(C1-C20)alkyl; and
[54] R6 is a halogen, (C1-C20)alkyl, halo(C1-C20)alkyl,
(C1-C20)alkoxy, (C6-C20)aryl, or (C3-C20)heteroaryl;
[55] A is -CO- or -SO 2 -;
[56] R7 is (C1-C20)alkyl, (C1-C20)alkoxy, (C6-C20)aryl,
(C1-C20)alkyl(C6-C20)aryl, or -NR 11 R1 2 ;
[57] R11 and R 1 2 are independently of each other hydrogen
or (C1-C20)alkyl; and
[58] n is an integer of 0 to 6.
[59] Preferably, in the method of preparing the compound
of Chemical Formula 1 according to an exemplary embodiment
of the present invention, the base may be any one or two or
more selected from NaOAc, Na 2 CO 3 , NaHNO 3 , Cu(OAc)2,
Cu(OAc)2.H20, and Net 3 , and may be used at 2 to 10 mol with
respect to 1 mol of the metal precursor compound of
Chemical Formula 3A.
[60] The quinoline-based compound of Chemical Formula 3B
according to an exemplary embodiment of the present
PLUS International IP Law Firm Our ref. PCT2018-151
invention may be used at 1.5 to 2.5 mol with respect to 1
mol of the metal precursor compound of Chemical Formula 3A.
[61] In another general aspect, a method of preparing a
gamma-lactam compound includes: amidating a dioxazol-one
compound in the presence of a metal complex represented by
the following Chemical Formula 1 and a base to prepare the
gamma-lactam compound:
[62] [Chemical Formula 1]
L
A-R7
[63] (Re)n
[64] wherein
[65] M is iridium, rhodium, ruthenium, or cobalt;
R3
[66] L is ~- or
[67] X is a halogen;
[68] R1 to R 5 are independently of one another hydrogen or
(Cl-C20)alkyl; and
[69] R6 is a halogen, (Cl-C20)alkyl, halo(Cl-C20)alkyl,
(Cl-C20)alkoxy, (C6-C20)aryl, or (C3-C20)heteroaryl;
[70] A is -CO- or -SO 2 -;
PLUS International IP Law Firm Our ref. PCT2018-151
[71] R7 is (C1-C20)alkyl, (C1-C20)alkoxy, (C6-C20)aryl,
(C1-C20)alkyl(C6-C20)aryl, or -NR11 R1 2 ;
[72] Rii and R12 are independently of each other hydrogen
or (C1-C20)alkyl; and
[73] n is an integer of 0 to 6.
[74] Preferably, the dioxazol-one compound according to an
exemplary embodiment of the present invention may be
represented by the following Chemical Formula 4, and the
gamma-lactam compound may be presented by the following
Chemical Formula 5:
[75] [Chemical Formula 4]
0 Ra 3 0
Ra5 R N RaR4
[76] Ra2
[77] [Chemical Formula 5]
Ra1 0 Ra 2 NH Ra3 / Ra6
[78] Ra5
[79] wherein
[80] Rai to Ra 6 are independently of one another hydrogen,
(Cl-C20)alkyl, (C3-C20)cycloalkyl, (C2-C20)alkenyl, (C2
C20)alkynyl, (Cl-C20)alkoxy, (C6-C20)aryl, (C3
C20)heteroaryl, or (C3-C20)heterocycloalkyl, or may be
PLUS International IP Law Firm Our ref. PCT2018-151
connected to an adjacent substituent to form an aromatic
ring, an alicyclic ring, or spiro ring with or without a
fused ring;
[81] the alkyl, the cycloalkyl, the alkenyl, the alkynyl,
the alkoxy, the aryl, the heteroaryl, the aromatic ring,
the alicyclic ring, or the spiro ring of Rai to Ra 6 may be
further substituted by any one or more substituents
selected from a halogen, nitro, cyano, (C1-C20)alkyl, (Cl
C20)alkenyl, (C1-C20)alkoxy, (C6-C20)aryl, (C6-C20)aryl(C1
C20)alkyl(C3-C20)heteroaryl, (C3-C20)heterocycloalkyl, and
-N (Raii) (Rai 2 ) ;
[82] Raii and Rai 2 are independently of each other hydrogen,
(C1-C20)alkyl, or (C1-C20)alkoxycarbonyl.
[83] Preferably, the base according to an exemplary
embodiment of the method of preparing a gamma-lactam
compound of the present invention may be one or two or more
selected from NaBArF4 (Sodium tetrakis [3, 5
bis(trifluoromethyl)phenyl]borate), AgSbF6 (Silver
hexafluoroantimonate(V)), AgNTf 2 (Silver
bis(trifluoromethanesulfonyl)imide), AgBF 4 (Silver
tetrafluoroborate), AgPF 6 (Silver hexafluorophosphate),
AgOTf (Silver trifluoromethanesulfonate), and AgOAc (Silver
acetate), and may be used at 0.01 to 0.1 mol with respect
to 1 mol of the dioxazol-one compound.
[84] The metal complex of Chemical Formula 1 according to
PLUS International IP Law Firm Our ref. PCT2018-151
an exemplary embodiment of the present invention may be
used as a catalyst and may be used at 0.01 to 0.1 mol with
respect to 1 mol of the dioxazol-one compound.
[85] Preferably, the amidation according to an exemplary
embodiment of the present invention may be performed at 20
to 60 0 C.
[86] Preferably, in Chemical Formula 1 according to an
exemplary embodiment of the method of preparing a gamma
lactam compound of the present invention, M may be iridium;
R3
R4 R2
L may be -- R ; X may be chloro; Ri to R 5 may be
independently of one another (C1-C20)alkyl; R 6 may be (Cl
C20)alkoxy; A may be -CO-; R7 may be (C1-C20)alkoxy; and n
may be an integer of 0 or 1.
[87] Preferably, in Chemical Formulae 4 and 5 according to
an exemplary embodiment of the method of preparing a gamma
lactam compound of the present invention, Rai to Ra6 may be
independently of one another hydrogen, (C1-C20)alkyl, (C3
C20)cycloalkyl, (C2-C20)alkenyl, (C2-C20)alkynyl, (C6
C20)aryl, (C3-C20)heteroaryl, or (C3-C20)heterocycloalkyl,
or connected to an adjacent substituent to form an aromatic
ring, an alicyclic ring, or a spiro ring with or without a
fused ring; the alkyl, the cycloalkyl, the alkenyl, the
PLUS International IP Law Firm Our ref. PCT2018-151
alkynyl, the aryl, the heteroaryl, the aromatic ring, the
alicyclic ring, or the spiro ring of Rai to Ra6 may be
further substituted by any one or more substituents
selected from a halogen, nitro, cyano, (C1-C20)alkyl, (Cl
C20)alkenyl, (Cl-C20)alkoxy, (C6-C20)aryl, (C6-C20)aryl(Cl
C20)alkyl (C3-C20)heteroaryl, (C3-C20)heterocycloalkyl, and
-N(Raii) (Rai2); and Raii and Rai 2 may be independently of each
other (Cl-C20)alkyl or (Cl-C20)alkoxycarbonyl.
[88] More preferably, Rai to Ra5 may be independently of
each other hydrogen, (Cl-C20)alkyl, or (C3
C20)heterocycloalkyl; Ra 6 may be independently of each
other hydrogen, (Cl-C20)alkyl, (C3-C20)cycloalkyl, (C2
C20)alkenyl, (C2-C20)alkynyl, (C6-C20)aryl, or (C3
C20)heteroaryl, or Ra5 and Ra6 may be connected to form a
(C5-C8)spiro ring, Ra 2 and Ra 3 may be connected with (C2
C10)alkenylene to form a (C6-C12)aromatic ring, and in this
case, Rai and Ra2 are absent, Ra3 and Ra6 may be connected to
each other to form a (C3-C20)alicyclic ring with or without
an aromatic ring, Ra3 and Ra4 and Ra6 may be connected to
each other to form a (C3-C20)alicyclic ring with or without
an aromatic ring; the alkyl of Rai to Ra 5 , and the alkyl,
the cycloalkyl, the alkenyl, the alkynyl, the aryl, or the
heteroaryl of Ra6 may be further substituted by any one or
more substituents selected from a halogen, nitro, cyano,
(Cl-C20)alkyl, (Cl-C20)alkenyl, (Cl-C20)alkoxy, (C6
PLUS International IP Law Firm Our ref. PCT2018-151
C20)aryl, (C6-C20)aryl(C1-C20)alkyl (C3
C20) heterocycloalkyl, and -N (Raii) (Rai2 ) ; and Raii and Ra 2 may
be independently of each other hydrogen, (C1-C20)alkyl, or
(C1-C20)alkoxycarbonyl.
[89] Specifically, the method of preparing a gamma-lactam
compound according to an exemplary embodiment of the
present invention may include amidating the dioxazol-one
compound of the following Chemical Formula 6 in the
presence of the compound represented by Chemical Formula 1
and the base to prepare a gamma-lactam compound of the
following Chemical Formula 7:
[90] [Chemical Formula 6]
0 Ra3
Ra 5 N R
[91] Ra 6 Ra2
[92] [Chemical Formula 7]
Ra1 0
NH Ra3' Ra6
[93] Ra5
[94] wherein
[95] Rai and Ra3 are independently of each other hydrogen,
(C1-C20)alkyl, or (C3-C20)heterocycloalkyl;
[96] Ra2 and Ra 5 are independently of each other hydrogen
PLUS International IP Law Firm Ourref.PCT2018-151
or (C1-C20)alkyl;
[97] Ra 6 is (Cl-C20)alkyl, (C3-C20)cycloalkyl, (C2
C20)alkenyl, (C2-C20)alkynyl, (C6-C20)aryl, or (C3
C20)heteroaryl;
[98] the alkyl, the cycloalkyl, the alkenyl, the alkynyl,
the aryl, and the heteroaryl of Ra 6 may be further
substituted by any one or more substituents selected from a
halogen, nitro, cyano, (C1-C20)alkyl, (C2-C20)alkenyl, (Cl
C20)alkoxy, (C6-C20)aryl, (C6-C20)aryl(C1-C20)alkyl, and
N (Raii) (Ral2) ; and
[99] Raii and Ra1 2 are independently of each other hydrogen,
(C1-C20)alkyl, or (C1-C20)alkoxycarbonyl.
[100] Specifically, the method of preparing a gamma-lactam
compound according to a second embodiment of the present
invention may include amidating the dioxazol-one compound
of the following Chemical Formula 8 in the presence of the
compound represented by Chemical Formula 1 and the base to
prepare a gamma-lactam compound of the following Chemical
Formula 9:
[101] [Chemical Formula 8]
0 0 A N ,
N
[102] Ra5 R 3 Ra 1
[103] [Chemical Formula 9]
PLUS International IP Law Firm Our ref. PCT2018-151
Ra1 0
Ra 3 NH A Ra 5
[104]
[105] wherein
[106] ring A is a (C3-C20)alicyclic ring with or without an
aromatic ring;
[107] Rai and Ra 3 are independently of each other hydrogen
or (C1-C20)alkyl, and Ra5 is hydrogen or (C2-C20)alkenyl;
[108] the alkyl of Rai and Ra3 and the alkenyl of Ra5 may be
further substituted by any one or more substituents
selected from a halogen, nitro, cyano, (C1-C20)alkyl, (C2
C20)alkenyl, (C1-C20)alkoxy, (C6-C20)aryl, (C6
C20)heteroaryl, (C3-C20)heterocycloalkyl, and -N(Ra 2 1) (Ra 2 2 );
and
[109] Ra 2 1 and Ra 2 2 are independently of each other hydrogen,
(C1-C20)alkyl, or (C1-C20)alkoxycarbonyl.
[110] Specifically, the method of preparing a gamma-lactam
compound of a third embodiment of the present invention may
include amidating the dioxazol-one compound of the
following Chemical Formula 10 in the presence of the
compound represented by Chemical Formula 1 and the base to
prepare a gamma-lactam compound of the following Chemical
Formula 11:
[111] [Chemical Formula 10]
PLUS International IP Law Firm Our ref. PCT2018-151
0 Ra 3
Rai )0 B N
[112] Ra2
[113] [Chemical Formula 11]
Rai 0 Ra 2 Ra 3 NH B
[114]
[115] wherein
[116] Rai to Ra 3 are independently of one another hydrogen
or (C1-C20)alkyl;
[117] ring B is an alicyclic ring; and
[118] the alkyl of Rai to Ra 3 and the alicyclic ring of ring
B may be further substituted by any one or more
substituents selected from a halogen, nitro, cyano, (Cl
C20)alkyl, (C2-C20)alkenyl, (C1-C20)alkoxy, (C6-C20)aryl,
and (C6-C20)aryl(C1-C20)alkyl.
[119] Specifically, the method of preparing a gamma-lactam
compound of a fourth embodiment of the present invention
may include amidating the dioxazol-one compound of the
following Chemical Formula 12 in the presence of the
compound represented by Chemical Formula 1 and the base to
prepare a gamma-lactam compound of the following Chemical
Formula 13:
PLUS International IP Law Firm Our ref. PCT2018-151
[120] [Chemical Formula 12]
0
N Ra6
[121] Ra5
[122] [Chemical Formula 13]
0
NH Ra6
[123] Ra5
[124] wherein
[125] Ra5 and Ra 6 are independently of each other hydrogen,
(C1-C20)alkyl, or (C6-C20)aryl.
[126] In still another general aspect, a gamma-lactam
compound represented by Chemical Formula 5 is provided.
[Advantageous Effects]
[127] The metal complex of the present invention adopts a
specific functional group as a ligand in a metal, and thus,
is very useful as a catalyst for preparing a gamma-lactam
compound from a dioxazol-one compound.
[128] Therefore, the method of preparing a gamma-lactam
compound using the metal complex of Chemical Formula 1 of
the present invention as a catalyst may easily produce a
high-purity gamma-lactam compound with high selectivity and
PLUS International IP Law Firm Our ref. PCT2018-151
yield from various dioxazol-one compounds, and thus, the
prepared gamma-lactam compound may be useful as a raw
material, an intermediate, and the like in various fields.
[Best Model
[129] Hereinafter, the novel metal complex of the present
invention, the method of preparing the same, and the method
of preparing a gamma-lactam compound from a dioxazol-one
compound using the same will be described in detail, but
the present invention is not limited thereto.
[130] "Alkyl", "alkoxy", and a substituent containing
"alkyl" described herein refer to a hydrocarbon radical in
a linear or branched form having 1 to 20 carbon atoms.
[131] "Alkenyl" described herein is an organic radical
derived from a hydrocarbon containing one or more double
bonds, and
[132] "alkynyl" described herein is an organic radical
derived from a hydrocarbon containing one or more triple
bonds.
[133] "Haloalkyl" described herein refers to one or more
hydrogens of the alkyl being substituted by one or more
halogens, preferably fluorines.
[134] "Cycloalkyl" described herein refers to a non
aromatic monocyclic or multicyclic ring system having 3 to
carbon atoms, and a monocyclic ring includes cyclopropyl,
cyclobutyl, cyclopentyl, and cyclohexyl, without limitation.
PLUS International IP Law Firm Our ref. PCT2018-151
An example of the multicyclic cycloalkyl group includes
perhydronaphthyl, perhydroindenyl, and the like; and a
bridged multicyclic cycloalkyl group includes adamantyl,
norbornyl, and the like.
[135] "Heterocycloalkyl" described herein refers to a non
aromatic monocyclic or multicyclic ring system having 3 to
carbon atoms containing 1 to 4 heteroatoms selected from
0 N 0
B, N, 0, S, P (=0) , Si, and P, and phthalimido
of the present invention is included therein.
[136] "Aryl" described herein is an organic radical derived
from an aromatic hydrocarbon by removal of one hydrogen,
including a monocyclic or fused ring system containing
appropriately 4 to 7, preferably 5 or 6 ring atoms in each
ring, and even including a form in which a plurality of
aryls are connected by a single bond. A specific example
includes phenyl, naphthyl, biphenyl, terphenyl, anthryl,
indenyl, fluorenyl, phenanthryl, triphenylenyl, pyrenyl,
perylenyl, crycenyl, naphthacenyl, fluoranthenyl, and the
like. Naphthyl includes 1-naphthyl and 2-naphthyl, anthryl
includes 1-anthryl, 2-anthryl, and 9-anthryl, and fluorenyl
includes all of 1-fluorenyl, 2-fluorenyl, 3-fluorenyl, 4
fluorenyl, and 9-fluorenyl.
[137] "Heteroaryl" described herein refers to an aryl group
PLUS International IP Law Firm Our ref. PCT2018-151
containing 1 to 4 heteroatoms selected from B, N, 0, S,
P(=O), Si, and P as an aromatic ring backbone atom, and
carbons as remaining aromatic ring backbone atoms, and is a
- or 6-membered monocyclic heteroaryl and a multicyclic
heteroaryl fused with one or more benzene rings, which may
be partially saturated. In addition, heteroaryl in the
present invention also includes a form in which one or more
heteroaryls are connected by a single bond.
[138] "Arylalkyl" described herein alone or as a portion of
another group refers to a functional group in which one or
more hydrogens of an aryl group are substituted with alkyl,
and as an example, may be methylphenyl or the like.
[139] A fused ring of an aromatic ring, an alicyclic ring,
or a spiro ring containing a fused ring described herein
may be an aromatic ring, an alicyclic ring, or a spiro ring,
preferably an aromatic ring or alicyclic ring, and
specifically a C6-C12 aromatic ring or a C1-C12 alicyclic
ring, but is not limited thereto.
[140] In addition, a "(C1-C20)alkyl group" described herein
is preferably (C1-C10)alkyl, and more preferably (Cl
C7)alkyl, a "(C3-C20)cycloalkyl group" is preferably (C3
C12)cycloalkyl, a "(C3-C20)heterocycloalkyl group" is
preferably (C3-C12)heterocycloalkyl, a "(C6-C20)aryl group"
is preferably (C6-C12)aryl, and a "(C3-C30)heteroaryl
group" is preferably (C3-C12)heteroaryl.
PLUS International IP Law Firm Our ref. PCT2018-151
[141] The present invention provides a novel metal complex,
and the metal complex of the present invention may be
useful as a catalyst for preparing gamma-lactam having
excellent activity and chemical selectivity and is
represented by the following Chemical Formula 1:
[142] [Chemical Formula 1]
L
-N, IA-Ry
[143] (R 6 )n
[144] wherein
[145] M is iridium, rhodium, ruthenium, or cobalt;
R3
R4 R2
[146] L is ~~ or
[147] X is a halogen;
[148] R1 to R 5 are independently of one another hydrogen or
(C1-C20)alkyl; and
[149] R 6 is a halogen, (C1-C20)alkyl, halo(C1-C20)alkyl,
(C1-C20)alkoxy, (C6-C20)aryl, or (C3-C20)heteroaryl;
[150] A is -CO- or -SO 2 -;
[151] R7 is (C1-C20)alkyl, (C1-C20)alkoxy, (C6-C20)aryl,
(C1-C20)alkyl(C6-C20)aryl, or -NR11R12;
PLUS International IP Law Firm Our ref. PCT2018-151
[152] R 11 and R1 2 are independently of each other hydrogen
or (C1-C20)alkyl; and
[153] n is an integer of 0 to 6.
[154] The novel metal complex of the present invention is a
catalyst of a gamma-lactam compound, has excellent
catalytic activity, and amidates a dioxazol-one compound
under mild conditions unlike conventional catalysts to
prepare a gamma-lactam compound with high selectivity and
yield.
[155] In terms of obtaining a gamma-lactam compound with
excellent selectivity and yield, in Chemical Formula 1, L
R3
R4 R2
R5 jR, may be -- . More preferably, in Chemical Formula
R3
R4 R2
1, L may be -- ; X may be Cl or Br; Ri to R 5 may be
independently of one another (C1-C20)alkyl; R6 may be
halo(C1-C20)alkyl or (C1-C20)alkoxy; and n may be an
integer of 0 to 6.
[156] More preferably, Chemical Formula 1 according to an
exemplary embodiment of the present invention may be
represented by the following Chemical Formula 2:
PLUS International IP Law Firm Our ref. PCT2018-151
[157] [Chemical Formula 2]
CH 3 H 3C OH 3
H3C CH 3
-N
A-Ry
[158] (R)
[159] wherein
[160] X is a halogen;
[161] R 6 is halo(Cl-C20)alkyl or (C1-C20)alkoxy;
[162] A is -CO- or -SO 2 -;
[163] R7 is (C1-C20)alkyl, (C1-C20)alkoxy, (C6-C20)aryl,
(C1-C20)alkyl(C6-C20)aryl, or -NR 1 1 R 12 ;
[164] R 11 and R1 2 are independently of each other hydrogen
or (C1-C20)alkyl; and
[165] n is an integer of 0 or 1.
[166] In terms of a more efficient reaction, preferably, in
Chemical Formula 2 according to an exemplary embodiment of
the present invention, A may be -CO-.
[167] In terms of a still more efficient reaction,
preferably, in Chemical Formula 2 according to an exemplary
embodiment of the present invention, A may be -CO-; R6 and
R7 may be independently of each other (C1-C20)alkoxy; n may
be an integer of 1, and the compound represented by
PLUS International IP Law Firm Our ref. PCT2018-151
Chemical Formula 1 of the present invention may be used as
a catalyst which may easily produce a gamma-lactam compound
from a dioxazol-one compound.
[168] The metal complex according to an exemplary
embodiment of the present invention has excellent catalytic
activity and significantly improved selectivity as compared
with conventional catalyst, by introducing a different
ligand from those of the conventional catalysts, and thus,
a gamma-lactam compound may be easily obtained with high
selectivity and yield.
[169] Furthermore, the metal complex according to an
exemplary embodiment of the present invention progresses an
amidation reaction under mild conditions, thereby allowing
mass production of a gamma-lactam compound which is very
useful as a raw material, an intermediate, and the like.
[170] In addition, the present invention provides a method
of preparing a metal complex represented by Chemical
Formula 1 including: reacting a metal precursor compound of
the following Chemical Formula 3A and a quinoline-based
compound of the following Chemical Formula 3B in the
presence of a base to prepare the metal complex of Chemical
Formula 1:
[171] [Chemical Formula 3A]
PLUS International IP Law Firm Our ref. PCT2018-151
L X-M-X X M-X
[172] L
[173] [Chemical Formula 3B]
(RO), HN
[174] "A-Ry
[175] wherein
[176] M is iridium, rhodium, ruthenium, or cobalt;
R3
R4R ) R2
[177] L is ~~ or
[178] X is independently of each other a halogen;
[179] Ri to R 5 are independently of one another hydrogen or
(C1-C20)alkyl; and
[180] R6 is a halogen, (C1-C20)alkyl, halo(C1-C20)alkyl,
(C1-C20)alkoxy, (C6-C20)aryl, or (C3-C20)heteroaryl;
[181] A is -CO- or -SO 2 -;
[182] R7 is (C1-C20)alkyl, (C1-C20)alkoxy, (C6-C20)aryl,
(C1-C20)alkyl(C6-C20)aryl, or -NR 11 R1 2 ;
[183] R11 and R12 are independently of each other hydrogen
or (C1-C20)alkyl; and
[184] n is an integer of 0 to 6.
PLUS International IP Law Firm Our ref. PCT2018-151
[185] Preferably, in the method of preparing the compound
of Chemical Formula 1 according to an exemplary embodiment
of the present invention, the base may be any one or two or
more selected from NaOAc, Na 2 CO 3 , NaHNO 3 , Cu(OAc)2,
Cu(OAc)2.H20, and NEt 3 , and more preferably any one or two
or more selected from NaOAc, Na 2 CO 3 , NaHNO 3 , and Net 3 , and
may be used at 2 to 10 mol, preferably 4 to 8 mol with
respect to 1 mol of the metal precursor compound of
Chemical Formula 3A.
[186] The quinoline-based compound of Chemical Formula 3B
according to an exemplary embodiment of the present
invention may be used at 1.5 to 2.5 mole, preferably 1.7 to
2.3 mol with respect to 1 mol of the metal precursor
compound of Chemical Formula 3A.
[187] In another general aspect, a method of preparing a
gamma-lactam compound includes: amidating a dioxazol-one
compound in the presence of a metal complex represented by
the following Chemical Formula 1 and a base to prepare the
gamma-lactam compound:
[188] [Chemical Formula 1]
L
A-R7
[189] (Re)n
PLUS International IP Law Firm Our ref. PCT2018-151
[190] wherein
[191] M is iridium, rhodium, ruthenium, or cobalt;
R3
R4 R2
[192] L is ~~ or
[193] X is a halogen;
[194] Ri to R 5 are independently of one another hydrogen or
(C1-C20)alkyl; and
[195] R6 is a halogen, (C1-C20)alkyl, halo(C1-C20)alkyl,
(C1-C20)alkoxy, (C6-C20)aryl, or (C3-C20)heteroaryl;
[196] A is -CO- or -SO 2 -;
[197] R7 is (C1-C20)alkyl, (C1-C20)alkoxy, (C6-C20)aryl,
(C1-C20)alkyl(C6-C20)aryl, or -NR 11 R 12 ;
[198] R 11 and R 1 2 are independently of each other hydrogen
or (C1-C20)alkyl; and
[199] n is an integer of 0 to 6.
[200] Preferably, the metal complex according to an
exemplary embodiment of the present invention may be
represented by the following Chemical Formula 1-1:
[201] [Chemical Formula 1-1]
PLUS International IP Law Firm Our ref. PCT2018-151
R3
R4 R2
R5 R, NN''~MX - N\s N A-Ry
[202] (R),
[203] wherein M, X, Ri to R7 , A, and n are as defined in
Chemical Formula 1.
[204] Preferably, the dioxazol-one compound according to an
exemplary embodiment of the present invention may be
represented by the following Chemical Formula 4, and the
gamma-lactam compound may be presented by the following
Chemical Formula 5:
[205] [Chemical Formula 4]
0 Ra3
Ra5 R R N Ra 4
[206] Ra6 Ra2
[207] [Chemical Formula 5]
Rai 0 Ra 2 1
NH Ra3''/ Rae a4aR
[208] Ra 5
[209] wherein
PLUS International IP Law Firm Our ref. PCT2018-151
[210] Rai to Ra6 are independently of one another hydrogen,
(C1-C20)alkyl, (C3-C20)cycloalkyl, (C2-C20)alkenyl, (C2
C20)alkynyl, (C1-C20)alkoxy, (C6-C20)aryl, (C3
C20)heteroaryl, or (C3-C20)heterocycloalkyl, or may be
connected to an adjacent substituent to form an aromatic
ring, an alicyclic ring, or spiro ring with or without a
fused ring;
[211] the alkyl, the cycloalkyl, the alkenyl, the alkynyl,
the alkoxy, the aryl, the heteroaryl, the aromatic ring,
the alicyclic ring, or the spiro ring of Rai to Ra6 may be
further substituted by any one or more substituents
selected from a halogen, nitro, cyano, (C1-C20)alkyl, (Cl
C20)alkenyl, (C1-C20)alkoxy, (C6-C20)aryl, (C6-C20)aryl(C1
C20)alkyl, (C3-C20)heteroaryl, (C3-C20)heterocycloalkyl,
and -N(Raii) (Rai 2 ); and
[212] Raii and Rai 2 are independently of each other hydrogen,
(C1-C20)alkyl, or (C1-C20)alkoxycarbonyl.
[213] The method of preparing a gamma-lactam compound of
the present invention may easily produce a gamma-lactam
compound unlike unstable conventional methods, by
introducing a dioxazol-one compound which is a specific
starting material as a starting material instead of
carbonylnitrenes which have been used as a conventional
starting material, and furthermore, may produce a gamma
lactam compound with high selectivity under mild conditions.
PLUS International IP Law Firm Our ref. PCT2018-151
[214] Besides, the method of preparing a gamma-lactam
compound of the present invention adopts a quinoline amine
compound which is not a conventionally used catalyst but a
specific ligand, thereby easily preparing a gamma-lactam
compound with high selectivity and yield under mild
conditions.
[215] Preferably, the base according to an exemplary
embodiment of the method of preparing a gamma-lactam
compound of the present invention may be one or two or more
selected from NaBArF4 (sodium tetrakis [3, 5
bis(trifluoromethyl)phenyl]borate), AgSbF 6 (silver
hexafluoroantimonate(V)), AgNTf 2 (silver
bis(trifluoromethanesulfonyl)imide), AgBF 4 (silver
tetrafluoroborate), AgPF 6 (silver hexafluorophosphate),
AgOTf (silver trifluoromethanesulfonate), and AgOAc (silver
acetate), preferably one or two or more selected from
NaBArF4 (sodium tetrakis [3, 5
bis(trifluoromethyl)phenyl]borate), AgSbF6, AgNTf2, and
AgBF 4 , and may be used at 0.01 to 0.1 mol, preferably 0.01
to 0.07 mol with respect to 1 mol of the dioxazol-one
compound.
[216] The metal complex according to an exemplary
embodiment of the present invention is used as a catalyst,
and may be used at 0.01 to 0.1 mol, preferably 0.01 to 0.07
mol with respect to 1 mol of the dioxazol-one compound.
PLUS International IP Law Firm Our ref. PCT2018-151
[217] Preferably, amidation according to an exemplary
embodiment of the present invention may be performed by
stirring at 20 to 60°C, preferably 30 to 50°C for 8 to 24
hours, preferably 10 to 15 hours.
[218] In the method of preparing a gamma-lactam compound
according to an exemplary embodiment of the present
invention, amidation may be performed under an organic
solvent, and it is not necessary to limit the organic
solvent as long as it dissolves the reaction material. As
the organic solvent according to an exemplary embodiment of
the present invention, one or more selected from
acetonitrile, dichloromethane, dichloroethane, nitromethane,
toluene, and benzene may be used, and considering
solubility and ease of removal of the reactant, one or more
selected from dichloromethane, dichloroethane, and
acetonitrile may be used as a solvent.
[219] Preferably, in Chemical Formula 1 according to an
exemplary embodiment of the method of preparing a gamma
lactam compound of the present invention, M may be iridium;
R3
R4 R2
L may be -- ; X may be chloro; Ri to R 5 may be
independently of one another (C1-C20)alkyl; R 6 may be (Cl
C20)alkoxy; A may be -CO-; R7 may be (C1-C20)alkoxy; and n
PLUS International IP Law Firm Our ref. PCT2018-151
may be an integer of 0 or 1.
[220] Preferably, in Chemical Formulae 4 and 5 according to
an exemplary embodiment of the method of preparing a gamma
lactam compound of the present invention, Rai to Ra5 may be
independently of each other hydrogen, (C1-C20)alkyl, or
(C3-C20)heterocycloalkyl; Ra 6 may be independently of each
other hydrogen, (C1-C20)alkyl, (C3-C20)cycloalkyl, (C2
C20)alkenyl, (C2-C20)alkynyl, (C6-C20)aryl, or (C3
C20)heteroaryl, or Ra5 and Ra6 may be connected to form a
(C5-C8)spiro ring, Ra2 and Ra3 may be connected with (C2
C10)alkenylene to form a (C6-C12)aromatic ring, and in this
case, Rai and Ra2 are absent, Ra3 and Ra6 may be connected to
each other to form a (C3-C20)alicyclic ring with or without
an aromatic ring, Ra3 and Ra4 and Ra6 may be connected to
each other to form a (C3-C20)alicyclic ring with or without
an aromatic ring; the alkyl of Rai to Ra 5 , and the alkyl,
the cycloalkyl, the alkenyl, the alkynyl, the aryl, or the
heteroaryl of Ra6 may be further substituted by any one or
more substituents selected from a halogen, nitro, cyano,
(C1-C20)alkyl, (C1-C20)alkenyl, (C1-C20)alkoxy, (C6
C20)aryl, (C6-C20)aryl(C1-C20)alkyl (C3
C20) heterocycloalkyl, and -N (Raii) (Ra12) ; and Raii and Rai 2 may
be independently of each other hydrogen, (C1-C20)alkyl, or
(C1-C20)alkoxycarbonyl.
[221] Preferably, a first embodiment of the method of
PLUS International IP Law Firm Our ref. PCT2018-151
preparing a gamma-lactam compound of the present invention
may include amidating the dioxazol-one compound of the
following Chemical Formula 6 in the presence of the
compound represented by Chemical Formula 1 and the base to
prepare a gamma-lactam compound of the following Chemical
Formula 7:
[222] [Chemical Formula 6]
0 Ra3
RaR N
[223] Ras Ra2
[224] [Chemical Formula 7]
Ra 2 1 NH Ra3~~~ Rae
[225] Ra5
[226] wherein
[227] Rai and Ra3 are independently of each other hydrogen,
(C1-C20)alkyl, or (C3-C20)heterocycloalkyl;
[228] Ra 2 and Ra 5 are independently of each other hydrogen
or (C1-C20)alkyl;
[229] Ra 6 is (Cl-C20)alkyl, (C3-C20)cycloalkyl, (C2
C20)alkenyl, (C2-C20)alkynyl, (C6-C20)aryl, or (C3
C20)heteroaryl;
[230] the alkyl, the cycloalkyl, the alkenyl, the alkynyl,
PLUS International IP Law Firm Our ref. PCT2018-151
the aryl, and the heteroaryl of Ra 6 may be further
substituted by any one or more substituents selected from a
halogen, nitro, cyano, (C1-C20)alkyl, (C2-C20)alkenyl, (Cl
C20)alkoxy, (C6-C20)aryl, (C6-C20)aryl(C1-C20)alkyl, and
N (Raii) (Rai2 ) ; and
[231] Raii and Ra 2 are independently of each other hydrogen,
(C1-C20)alkyl, or (C1-C20)alkoxycarbonyl.
[232] Preferably, a second embodiment of the gamma-lactam
compound of the present invention may be prepared by
including amidating the dioxazol-one compound of the
following Chemical Formula 8 in the presence of the
compound represented by Chemical Formula 1 and the base to
prepare a gamma-lactam compound of the following Chemical
Formula 9:
[233] [Chemical Formula 8]
0 O A N0 N
[234] Ra 5 Ra 3 Ra1
[235] [Chemical Formula 9]
Ra1 0
Ra 3 NH A Ra 5
[236]
[237] wherein
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[238] ring A is a (C3-C20)alicyclic ring with or without an
aromatic ring;
[239] Rai and Ra3 are independently of each other hydrogen
or (C1-C20)alkyl, and Ra 5 is hydrogen or (C2-C20)alkenyl;
[240] the alkyl of Rai and Ra 3 and the alkenyl of Ra5 may be
further substituted by any one or more substituents
selected from a halogen, nitro, cyano, (C1-C20)alkyl, (C2
C20)alkenyl, (C1-C20)alkoxy, (C6-C20)aryl, (C6
C20)heteroaryl, (C3-C20)heterocycloalkyl, and -N(Ra 2 1) (Ra 2 2 );
and
[241] Ra 2 1 and Ra 2 2 are independently of each other hydrogen,
(C1-C20)alkyl, or (C1-C20)alkoxycarbonyl.
[242] Preferably, a third embodiment of the gamma-lactam
compound of the present invention may be prepared by
including amidating the dioxazol-one compound of the
following Chemical Formula 10 in the presence of the
compound represented by Chemical Formula 1 and the base to
prepare a gamma-lactam compound of the following Chemical
Formula 11:
[243] [Chemical Formula 10]
0 Ra3 Rai )0 B N
[244] Ra2
[245] [Chemical Formula 11]
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Rai 0 Ra 2 Ra 3 NH B
[246]
[247] wherein
[248] Rai to Ra 3 are independently of one another hydrogen
or (C1-C20)alkyl;
[249] ring B is an alicyclic ring; and
[250] the alkyl of Rai to Ra 3 and the alicyclic ring of ring
B may be further substituted by any one or more
substituents selected from a halogen, nitro, cyano, (Cl
C20)alkyl, (C2-C20)alkenyl, (C1-C20)alkoxy, (C6-C20)aryl,
and (C6-C20)aryl(C1-C20)alkyl.
[251] Preferably, a fourth embodiment of the gamma-lactam
compound of the present invention may be prepared by
including amidating the dioxazol-one compound of the
following Chemical Formula 12 in the presence of the
compound represented by Chemical Formula 1 and the base to
prepare a gamma-lactam compound of the following Chemical
Formula 13:
[252] [Chemical Formula 12]
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0
N Ra6
[253] Ra5
[254] [Chemical Formula 13]
0
NH Ra6
[255] Ra5
[256] wherein
[257] Ra5 and Ra6 are independently of each other hydrogen,
(C1-C20)alkyl, or (C6-C20)aryl.
[258] In addition, the present invention provides a gamma
lactam compound represented by Chemical Formula 5.
[259] Hereinafter, the constitution of the present
invention will be described in detail by the Examples, and
the following Examples are for better understanding of the
present invention, but the scope of the present invention
is not limited thereto.
[260] Preparation Example I: Preparation of quinoline
ligand
[261] Method 1.
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1) TCCA (37 mol%) 125 °C, 1 h 2) Quinoline N-Oxide
m O [RhCpCl 2J2 (2mol%) R -R2 Zn dust (9 equiv) R N4 NH 0 AgNTf2 (8 moi %) Me,0 NH 0 THF/ 30% NH4 CI (aq) =1:1 me,O NH AgOAc (1.1 equiv)/ 50 C, 12 h O rt, 1 h 0 0
[262] 1-1 1-2
[263] Methyl carbamate (1.1 mmol, 1.1 equivalents to
quinoline N-oxide, 82.5 mg), trichloroisocyanuric acid
(TCCA, 86 mg, 0.36 mmol, 37 mol%), and MeOH (2 mL) were
added to a vial and the mixture was stirred at 25°C for 1
hour. Quinoline N-oxide (1.0 mmol), [RhCp*Cl2]2 (Cp*:
pentamethylcyclopentadienyl) (12.5 mg, 0.02 mmol, 2 mol%),
AgNTf2 (31 mg, 0.08 mmol, 8 mol%), AgOAc (183.5 mg, 1.1
mmol), and MeOH (1 mL) were added thereto again and the
mixture was stirred at 50°C for 12 hours. After the
reaction was completed, the reaction mixture was filtered
with celite (dichloromethane (15 mLx3)). After the solvent
was removed by distillation under reduced pressure,
separation and purification were performed by column
chromatography (dichloromethane/methanol = 30:1 to 10:1) to
obtain compound 1-1 as a title compound.
[264] Compound 1-1 was dissolved in THF (15 mL), an aqueous
% NH 5 Cl solution (15 mL) and zinc dust (0.59 g, 9 mmol)
were added thereto, and the mixture was stirred at room
temperature for 1 hour. Thereafter, H2 0 (50 mL) was added
to the reaction mixture, extraction was performed with
EtOAc (50 mL x 3), and drying was performed with MgSO 4 to
remove residual moisture. After the solvent was removed by
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distillation under reduced pressure, separation and
purification were performed by column chromatography
(eluent: n-hexane/EtOAc = 4:1 to 1:1) to prepare quinoline
ligand compound 1-2.
[265] The following quinoline ligand compound was prepared
in the same manner as in the above, except that a starting
material having different substituents was used.
[266] [Preparation Example 1] Preparation of methyl
quinolin-8-ylcarbamate
N NH Me'O 0
[267] White solid (0.12 g, 61%, 2 steps
yield) ; m.p. 65-67°C; 'H NMR (600 MHz, CDCla) 5 9.21 (s,
1H), 8.78 (d, J = 4.2 Hz, 1H), 8.42 (d, J = 6.3 Hz, 1H),
8.13 (dd, J = 8.2, 1.5 Hz, 1H), 7.53 (t, J = 8.0 Hz, 1H),
7.47-7.40 (m, 2H), 3.85 (s, 3H); 13 C NMR (150 MHz, CDCl3) 5
154.1, 148.1, 138.2, 136.2, 134.7, 128.0, 127.3, 121.6,
120.6, 114.5, 52.3; IR (cm-1) 3358, 1728, 1524, 1486, 1200;
HRMS (EI) m/z calcd. for C11HioN 2 0 2 [M]+: 202.0742, found:
202.0741.
[268] [Preparation Example 2] Preparation of methyl (4
methoxyquinolin-8-yl)carbamate
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OMe
NN NH Me'0 0
[269] White solid (0.13 g, 56%, 2 steps
yield); m.p. 151-153°C; 1H NMR (600 MHz, CDCla) 5 9.21 (s,
1H), 8.63 (d, J = 5.2 Hz, 1H), 8.41 (d, J = 6.6 Hz, 1H),
7.80 (d, J = 9.6 Hz, 1H), 7.47 (t, J = 8.1 Hz, 1H), 6.77 (d,
J = 5.2 Hz, 1H), 4.05 (s, 3H), 3.84 (s, 3H); 13 C NMR (150
MHz, CDCl3) 5 162.5, 154.1, 149.1, 139.1, 134.4, 126.1,
121.0, 114.9, 114.6, 100.6, 55.8, 52.2; IR (cm-1) 3366,
1719, 1527, 1411, 1232, 1023, 753, 634; HRMS (EI) m/z calcd.
for C1 2 H1 2 N 2 0 3 [M]+: 232.0848, found: 232.0845.
[270] [Preparation Example 3] Preparation of methyl (6
methoxyquinolin-8-yl)carbamate
MeO
N NH Me'O 0
[271] White solid (0.18 g, 76%, 2 steps yield); m.p. 82-84°C; 'H NMR (600 MHz, CDCl,) 6 9.17 (s,
1H), 8.62 (dd, J = 4.1, 1.4 Hz, 1H), 8.14 (s, 1H), 8.01 (d,
J = 8.2 Hz, 1H), 7.38 (dd, J = 8.2, 4.2 Hz, 1H), 6.74 (d, J
= 2.5 Hz, 1H), 3.92 (s, 3H), 3.85 (s, 3H); 13C NMR (150 MHz,
CDCl 3 ) 5 158.5, 153.9, 145.5, 135.7, 134.9, 129.0, 122.0,
110.0, 107.1, 98.8, 55.5, 52.3; IR (cm-1) 3364, 1728, 1529,
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1221; HRMS (EI) m/z calcd. for C 1 2 H 1 2 N 2 03 [M]+: 232.0848,
found: 232.0851.
[272] [Preparation Example 4] Preparation of methyl (5
methoxyquinolin-8-yl)carbamate
OMe OMe 0 THF + AMe + NaHCO 3 0 N CI OM °C tort, 12h N NH 2 Me 0
[273] 1-3
[274] 8-amino-5-methoxyquinoline (0.87 g, 5 mmol) and
sodium bicarbonate (0.46 g, 5.5 mmol) were added to dried
THF (20 mL) and cooled to 0°C using an ice-bath, methyl
chloroformate (0.42 mL, 5.5 mmol) was slowly added, and the
reaction mixture was stirred at room temperature for 12
hours. The reaction mixture was filtered with celite
(dichloromethane (15 mLx3)), distilled under reduced
pressure, and separated and purified by column
chromatography (eluent: n-hexane/EtOAc = 4:1) to obtain
quinoline ligand compound 1-3.
[275] Light brown solid (0.95 g, 84%); m.p. 118-120°C; 1H
NMR (600 MHz, CD 2 Cl 2 ) 5 8.86 (s, 1H), 8.78 (d, J = 4.0 Hz,
1H), 8.54 (d, J = 9.8 Hz, 1H), 8.26 (d, J = 7.0 Hz, 1H),
7.43 (dd, J= 8.4, 4.2 Hz, 1H), 6.85 (d, J= 8.5 Hz, 1H),
3.96 (s, 3H), 3.78 (s, 3H); 13 C NMR (150 MHz, CD2Cl2) 5
154.0, 149.7, 148.7, 138.8, 131.0, 128.0, 120.8, 120.5,
114.3, 104.3, 55.7, 52.0; IR (cm-1) 3366, 1719, 1524, 1493,
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1221, 1086, 837, 604; HRMS (EI) m/z calcd. for C1 2 H1 2 N 2 03
[M]+: 232.0848, found: 232.0848.
[276] [Preparation Example 5] Preparation of methyl (5
(trifluoromethyl)quinolin-8-yl)carbamate
CF 3
F 3C-1-0 1,2-DCE | + CuCI + > 'N ( N +CC+-O 0 rt, 18 h 0NN MO NH Me' Y Me 0
[277] 0 1-4
[278] After methyl quinolin-8-ylcarbamate (404 mg, 2 mmol)
was dissolved in 1,2-dichloroethane (20 mL) in a 100 mL
round flask, CuCl (9.9 mg, 0.1 mmol, 5.0 mol%) and 1
trifluoromethyl-1,2-benziodoxol-3 (1H) -one (632 mg, 2 mmol)
were added thereto and the mixture was stirred at 250C for
18 hours. After the reaction was completed, the solvent was
removed, and separation and purification were performed by
column chromatography (n-hexane/ethyl acetate = 10/1) to
obtain desired quinoline ligand compound 1-4.
[279] White solid (147 mg, 27%); m.p. 114-116°C; 1H NMR
(600 MHz, CDCl3) 5 9.41 (s, 1H), 8.85 (d, J = 4.0 Hz, 1H),
8.48 (d, J = 8.6 Hz, 1H), 8.44 (d, J = 8.0 Hz, 1H), 7.90 (d,
J = 8.2 Hz, 1H), 7.57 (dd, J = 8.6, 4.1 Hz, 1H), 3.88 (s,
3H); 13C NMR (150 MHz, CDCla) 5 153.8, 148.5, 138.4, 137.9,
133.0 (q, J = 2.4 Hz), 126.4 (q, J = 5.8 Hz), 124.3 (q, J =
272.4 Hz), 124.3, 122.8, 118.7 (q, J = 31.0 Hz), 112.1,
52.6; 19 F NMR (564 MHz, CDCl3) 5 -58.70 (s); IR (cm-1) 3370,
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1735, 1529, 1316, 1086, 858; HRMS (EI) m/z calcd. for
C 1 2 H9 F 3 N 2 0 2 [M]+: 270.0616, found: 270.0613.
[280] Example I: Preparation of metal complex
[281] [Examples 1 to 4] Preparation of metal complexes C to
F
+ N~ DCM
T
[282] (T= NR)
[283] [IrCp*Cl2]2 (Cp*: pentamethylcyclopentadienyl) (0.20 g,
0.25 mmol), a quinoline ligand compound (0.50 mmol), sodium
acetate (0.12 g, 1.5 mmol), and dichloromethane (10 mL)
were added to a vial and the mixture was stirred at room
temperature for 12 hours. After the reaction was completed,
the reaction mixture was filtered with celite
(dichloromethane (15 mLx3)), the solvent was removed by
distillation under reduced pressure, and separation and
purification were performed by column chromatography (n
hexane/acetone = 2:1 to 1:1) to prepare metal catalysts C
to F.
[284] [Example 1] 8-(N-Tosyl)aminoquinoline bound Cp*
iridium complex (metal catalyst C)
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N- r4CI N" I rCI
N' N.Ts
[285] Orange solid (0.22 g, 66%); 1H NMR
(600 MHz, CDCl3 ) o 8.66 (d, J = 5.0 Hz, 1H), 8.10 (d, J =
8.3 Hz, 2H), 7.98 (d, J= 8.3 Hz, 1H), 7.39 (dd, J = 8.3,
5.1 Hz, 1H), 7.34 (d, J= 8.0 Hz, 1H), 7.22 (t, J = 8.0 Hz,
1H), 7.04 (d, J = 8.1 Hz, 2H), 6.89 (d, J = 8.0 Hz, 1H),
2.22 (s, 3H), 1.68 (s, 15H); 13 C NMR (150 MHz, CDCl3) 6
149.3, 147.3, 145.2, 141.3, 138.0, 137.4, 129.7, 129.0,
128.9, 128.7, 122.2, 118.0, 116.6, 87.3 (Cp*), 21.3, 9.3
(Cp*); IR (cm-1) 3051, 1462, 1375, 1299, 1138, 869, 655,
572; HRMS (EI) m/z calcd. for C 2 6 H 2 8ClIrN 2 0 2 S [M]+: 660.1189,
found: 660.1187.
[286] [Example 2] 8-(N-Benzylamino)quinoline bound Cp*
iridium complex (metal catalyst D)
N-rCI N Ph
[287] Orange solid (0.22 g, 70%); 1H NMR
(400 MHz, CDCl3) 6 8.67 (d, J = 4.9 Hz, 1H), 8.03 (d, J =
8.3 Hz, 1H), 7.91 (d, J= 7.7 Hz, 2H), 7.38 (d, J= 7.8 Hz,
2H), 7.28- 7.22 (m, 3H), 7.19 (t, J = 8.0 Hz, 1H), 6.98 (d,
PLUS International IP Law Firm Our ref. PCT2018-151
J = 7.9 Hz, 1H), 1.45 (s, 15H); 13 C NMR (150 MHz, CDCl 3 ) 5
177.6, 151.7, 148.8, 145.8, 140.2, 137.8, 130.0, 129.7,
129.4, 128.8, 127.7, 122.5, 122.0, 117.1, 86.9 (Cp*), 8.9
(Cp*) ; IR (cm-1) 2914, 1599, 1501, 1373, 1316; HRMS (EI) m/z
calcd. for C 2 6 H 2 6 ClIrN 2 0 [M]+: 610.1363, found: 610.1367.
[288] [Example 3] 8-(N-Acetylamino)quinoline bound Cp*
iridium complex (metal catalyst E)
N r Cl N '00
[289] Yellow solid (0.19 g, 68%); 'H NMR
(600 MHz, CDCl 3 ) 5 8.84 (d, J = 8.0 Hz, 1H), 8.59 (d, J =
4.9 Hz, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.50 (t, J= 8.0 Hz,
1H), 7.38 (dd, J = 8.2, 5.0 Hz, 1H), 7.14 (d, J = 8.0 Hz,
1H), 2.59 (s, 3H), 1.50 (s, 15H); 13 C NMR (150 MHz, CDCl 3 ) 5
177.1, 150.2, 149.6, 146.3, 138.0, 129.8, 128.9, 123.3,
121.9, 118.4, 86.6 (Cp*), 28.8, 8.7 (Cp*); IR (cm-1)1602,
1492, 1365, 1315, 829, 762; HRMS (EI) m/z calcd. for
C 2 1H 2 4 ClIrN 2 0 [M]+: 548.1206, found: 548.1204.
[290] [Example 4] 8-[N-(tert
Butyloxycarbonyl)amino]quinoline bound Cp*-iridium complex
(metal catalyst F)
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N. r4CI -- N.B N.Boc
[291] Orange solid (0.21 g, 70%); 1H NMR (600
MHz, CDCl 3 ) o 8.61-8.57 (m, 1H), 8.35 (d, J = 8.0 Hz, 1H),
8.01-7.95 (m, 1H), 7.47 (t, J= 8.0 Hz, 1H), 7.34 (dd, J=
8.3, 5.0 Hz, 1H), 7.02 (d, J= 7.9 Hz, 1H), 1.56 (s, 24H);
3 1 C NMR (150 MHz, CDCl3) 6 158.6, 151.4, 149.4, 146.4, 137.6,
129.4, 129.1, 122.4, 121.8, 116.5, 86.2 (Cp*), 78.6, 28.9,
8.9 (Cp*); IR (cm-1) 2970, 1652, 1447, 1296, 1154, 1108, 993,
761; HRMS (EI) m/z calcd. for C 2 4 H 3 0 ClIrN 2O 2 [M]+: 606.1625,
found: 606.1627.
[292] [Examples 5 to 10] Preparation of metal complexes G
to L
DCM
[IrCp*Cl 2] 2 + R -R1 N + Na 2 CO 3 rt,12 h Rr,'C TT
[293] (T= NR) R2
[294] [IrCp*Cl 2 ] 2 (Cp*: pentamethylcyclopentadienyl) (0.20 g,
0.25 mmol), a quinoline ligand compound (0.50 mmol), sodium
carbonate (0.16 g, 1.50 mmol), and dichloromethane (10 mL)
were added to a vial and the mixture was stirred at room
temperature for 12 hours. After the reaction was completed,
the reactants were filtered with celite (dichloromethane
PLUS International IP Law Firm Our ref. PCT2018-151
(15 mLx3)), the solvent was removed by distillation under
reduced pressure, and separation and purification were
performed by column chromatography (n-hexane/acetone = 2:1
to 1:1) to prepare metal catalysts G to L.
[295] [Example 5] 8-[N-(Methyloxycarbonyl)amino]quinoline
bound Cp*-iridium complex (metal catalyst G)
Ir N-- rCI -' N OMe
[296] Yellow solid (0.24 g, 84%) ; 'H NMR
(600 MHz, CDCl 3 ) 5 8.64 (dd, J= 10.2, 6.6 Hz, 2H), 8.05 (d,
J = 8.2 Hz, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.34 (dd, J =
8.2, 5.1 Hz, 1H), 7.09 (d, J= 7.9 Hz, 1H), 3.75 (s, 3H),
1.57 (s, 15H); 13C NMR (150 MHz, CDCl3) 5 159.7, 150.7,
148.9, 145.8, 137.8, 129.7, 129.5, 121.8, 121.7, 117.1,
86.6 (Cp*), 52.6, 8.9 (Cp*); IR (cm-1) 1645, 1500, 1376,
1302, 1174, 1030, 831; HRMS (EI) m/z calcd. for
C 2 1H 24 ClIrN 2 0 2 [M]+: 564.1156, found: 564.1157.
[297] [Example 6] 8-[N-(N,N
Dimethylaminocarbonyl)amino]quinoline bound Cp*-iridium
complex (metal catalyst H)
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IrN N'- rCI N NMe 2
[298] Red solid (0.15 g, 51%); 1H NMR (400
MHz, CDCla) 5 8.47 (d, J = 5.0 Hz, 1H), 7.92 (d, J = 8.4 Hz,
1H), 7.34-7.28 (m, 2H), 6.93 (d, J = 8.0 Hz, 1H), 6.68 (d,
J = 7.9 Hz, 1H), 3.17 (s, 6H), 1.62 (s, 15H); 13 C NMR (150
MHz, CDCl3 , two carbons merged to others) 5 166.5, 154.8,
147.0, 145.0, 137.7, 130.5, 129.9, 121.7, 115.6, 111.6,
86.0 (Cp*), 8.4 (Cp*); IR (cm-1) 2910, 1622, 1460, 1358,
1327, 1150, 811, 772; HRMS (EI) m/z calcd. for C 2 2H 27 ClIrN 3O
[M]+: 577.1472, found: 577.1475.
[ 29 9 ] [Example 7] 8-[N-(Methyloxycarbonyl)amino]-5
trifluoromethyl quinoline bound Cp*-iridium complex (metal
catalyst I)
N'- r CI N OMe F3C 0
[300] Orange solid (0.22 g, 70%); 1H NMR
(600 MHz, CDCla) o 8.73 (d, J = 5.1 Hz, 1H), 8.61 (d, J =
8.6 Hz, 1H), 8.37 (d, J = 8.7 Hz, 1H), 7.86 (d, J = 8.7 Hz,
1H), 7.49 (dd, J = 8.7, 5.1 Hz, 1H), 3.77 (s, 3H), 1.57 (s,
H); 13C NMR (150 MHz, CDCl3) 6 159.6, 154.4, 149.6, 145.8,
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134.6, 128.7 (q, J = 5.2 Hz), 126.2, 124.2 (q, J = 271.9
Hz), 123.0, 119.0, 115.0 (q, J = 31.4 Hz), 86.9 (Cp*), 52.9,
8.9 (Cp*); 1 9F NMR (564 MHz, CDCl3) 5 -58.08 (s); IR (cm-1)
1660, 1511, 1314, 1285, 1133, 1098, 847; HRMS (EI) m/z
calcd. for C 2 2 H 2 3ClF 3 IrN 20 2 [M]+: 632.1029, found: 632.1031.
[301] [Example 8] 4-Methoxy-8-[N
(methyloxycarbonyl)amino]quinoline bound Cp*-iridium
complex (metal catalyst J)
N'- IrC MeO NOMe / Oe
[302] Yellow solid (0.24 g, 80%); 'H
NMR (600 MHz, CDCl 3 ) 5 8.65 (d, J = 8.0 Hz, 1H), 8.52 (d, J
= 6.0 Hz, 1H), 7.43 (t, J = 8.1 Hz, 1H), 7.33 (d, J = 8.8
Hz, 1H), 6.50 (d, J = 6.0 Hz, 1H), 3.80 (s, 3H), 3.75 (s,
3H), 1.55 (s, 15H); 13 C NMR (150 MHz, CDCl3) 5 163.5, 159.8,
150.4, 150.3, 146.0, 128.4, 121.9, 121.7, 111.4, 101.7,
86.1 (Cp*), 56.1, 52.6, 8.9 (Cp*); IR (cm-1) 1641, 1513,
1410, 1308, 1198, 1028, 750; HRMS (EI) m/z calcd. for
C 2 2 H 2 6 ClIrN 2 0 3 [M]+: 594.1261, found: 594.1261.
[303] [Example 9] 5-Methoxy-8-[N
(methyloxycarbonyl)amino]quinoline bound Cp*-iridium
complex (metal catalyst K)
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N .OMe MeO 0
[304] Orange solid (0.27 g, 91%); 1H NMR
(600 MHz, CDCl3 ) o 8.66 (d, J = 4.8 Hz, 1H), 8.59 (d, J =
8.8 Hz, 1H), 8.46 (d, J = 8.4 Hz, 1H), 7.35 (dd, J = 8.3,
5.0 Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 3.96 (s, 3H), 3.73
(s, 3H), 1.56 (s, 15H); 13C NMR (150 MHz, CDCl3 ) 5 159.6,
149.6, 147.5, 145.9, 143.9, 132.9, 121.2, 120.9, 120.8,
107.2, 86.4 (Cp*), 56.2, 52.5, 8.9 (Cp*); IR (cm-1) 1645,
1571, 1470, 1378, 1323, 1295, 1093; HRMS (EI) m/z calcd.
for C 22 H 2 6ClIrN 20 3 [M]+: 594.1261, found: 594.1260.
[305] [Example 10] 6-Methoxy-8-[N
(methyloxycarbonyl)amino]quinoline bound Cp*-iridium
complex (metal catalyst L)
N rCI N OMe 0 MeO
[306] Yellow solid (0.24 g, 81%); 1H NMR
(600 MHz, CDCl3 ) o 8.45 (d, J = 5.0 Hz, 1H), 8.39 (d, J=
2.3 Hz, 1H), 7.90 (d, J = 8.3 Hz, 1H), 7.29-7.24 (m, 1H),
6.51 (d, J= 2.2 Hz, 1H), 3.89 (s, 3H), 3.75 (s, 3H), 1.56
(s, 15H); 13C NMR (150 MHz, CDCl3) 6 160.9, 159.7, 151.8,
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146.2, 142.8, 136.2, 129.7, 122.2, 112.2, 97.2, 86.5 (Cp*),
55.7, 52.7, 8.9 (Cp*); IR (cm-1) 1637, 1572, 1497, 1378,
1296, 1258, 1054, 724; HRMS (EI) m/z calcd. for
C 2 2 H 2 6 ClIrN 2 0 3 [M]+: 594.1261, found: 594.1260.
[307] [Example 11] Preparation of metal complex M
[308] [Ru(p-cymene)Cl2]2 (122 mg, 0. 20mmol) , methyl (5
methoxyquinolin-8-yl)carbamate (92 mg, 0.40mmol), sodium
carbonate (126 mg, 1.50 mmol), and dichloromethane (10 mL)
were added to a vial and the mixture was stirred at room
temperature for 12 hours. After the reaction was completed,
the reaction mixture was filtered with celite and washed
(dichloromethane (15 mLx3)), the solvent was removed under
reduced pressure, and the residue was separated and
purified by column chromatography (n-hexane/acetone = 2:1
to 1:1) to prepare the following metal catalyst M.
[309] 5-Methoxy-8-[N- (methyloxycarbonyl) amino] quinoline
bound p-cymene-ruthenium complex (metal catalyst M)
Ru N OMe MeO O
[310] Orange solid (150 mg, 75%); 1H NMR
(600 MHz, CDCl3) o 9.07 (d, J = 4.8 Hz, 1H), 8.70 (d, J =
8.8 Hz, 1H), 8.48 (d, J= 8.2 Hz, 1H), 7.32 (dd, J = 8.2,
5.1 Hz, 1H), 6.87 (d, J= 8.8 Hz, 1H), 5.71 (d, J = 5.9 Hz,
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1H), 5.31 (d, J = 5.9 Hz, 1H), 5.24 (t, J = 6.2 Hz, 2H),
3.91 (s, 3H), 3.80 (s, 3H), 2.46 (hept, J = 7.0 Hz, 1H),
2.29 (s, 3H), 0.96 (d, J = 6.9 Hz, 3H), 0.87 (d, J = 6.8 Hz,
3 3H); 1 C NMR (150 MHz, CDCla) 5 160.8, 151.4, 146.6, 145.0,
143.6, 132.6, 120.8, 120.7, 120.6, 107.5, 103.1, 100.1,
86.2, 84.5, 82.9, 82.7, 56.2, 52.1, 30.8, 22.2, 22.0, 19.0.
[311] [Example 12] Preparation of metal complex N
[312] [RhCp*Cl2]2 (77mg, 0.125 mmol), methyl (5
methoxyquinolin-8-yl)carbamate (58 mg, 0.25 mmol), sodium
carbonate (79.5 mg, 0.75 mmol), and dichloromethane (5 mL)
were added to a vial and the mixture was stirred at room
temperature for 12 hours. After the reaction was completed,
the reaction mixture was filtered with celite and washed
(dichloromethane (15 mL x 3)), the solvent was removed
under reduced pressure, and recrystallization was performed
0 with a small amount of acetone at -30 C to prepare the
following metal catalyst N.
[313] 5-Methoxy-8-{N- (methyloxycarbonyl) amino Iquinoline
bound Cp*-rhodium complex (metal catalyst N)
Rh 'N- A C1 N OMe MeO O
[314] Orange solid (90 mg, 71%); 'H NMR
(600 MHz, CDCl3) 5 8.71 (d, J = 4.9 Hz, 1H), 8.60 (d, J=
PLUS International IP Law Firm Our ref. PCT2018-151
8.7 Hz, 1H), 8.51 (d, J = 8.3 Hz, 1H), 7.39 (dd, J= 8.4,
5.0 Hz, 1H), 6.89 (d, J = 8.7 Hz, 1H), 3.93 (s, 3H), 3.73
(s, 3H), 1.54 (s, 15H); 13 C NMR (150 MHz, CDCl3) 5 160.3,
150.0, 146.9, 145.5, 143.3, 132.9, 121.1, 120.9, 120.7,
107.4, 94.5, 94.4, 56.2, 52.0, 8.9.
[315] [Example 13] Preparation of metal complex 0
[316] [CoCp*Cl2]2 (66 mg, 0.125 mmol), methyl (5
methoxyquinolin-8-yl)carbamate (58 mg, 0.25 mmol),
potassium hydroxide (42 mg, 0.75 mmol), and dichloromethane
(5 mL) were added to a vial and the mixture was stirred at
room temperature for 12 hours. After the reaction was
completed, the reaction mixture was filtered with celite
and washed (dichloromethane (15 mL x 3)), the solvent was
removed under reduced pressure, and recrystallization was
0 performed with a small amount of acetone at -30 C to
prepare the following metal catalyst 0.
[317] 5-Methoxy-8-{N- (methyloxycarbonyl) amino Iquinoline
bound Cp*-cobalt complex (metal complex 0)
Co NA 'CI N OMe MeO O
[318] Green solid (34 mg, 30%); 1H NMR
(600 MHz, CD 2 Cl 2 ) 5 9.24 (dd, J = 5.1, 1.4 Hz, 1H), 8.53
(dd, J = 8.4, 1.4 Hz, 1H), 8.36 (d, J = 8.6 Hz, 1H), 7.56
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(dd, J= 8.4, 5.1 Hz, 1H), 6.88 (d, J = 8.6 Hz, 1H), 3.95
(s, 3H), 3.73 (s, 3H), 1.10 (s, 15H).
[319] [Comparative Example 1] Preparation of metal complex
A
;NX Acetone
[IrCp*Cl21 2 + / OH + NaHCO 3 ,-Ir reflux,2h N h CI
[320 ]
[321] [IrCp*Cl 2 ]2 (0.4106 g, 0.5154 mmol), 2-(2'-pyridyl)-2
propanol (0.1420 g, 1.036 mmol), sodium bicarbonate (0.345
g, 4.11 mmol), and acetone (50 mL) were added to a vial and
the mixture was stirred at room temperature for 2 hours.
After the reaction was completed, the reactants were
filtered with celite (dichloromethane (15 mLx3)), the
solvent was removed by distillation under reduced pressure,
and separation and purification were performed by column
chromatography (n-hexane/acetone = 2:1 to 1:1) to prepare
metal catalyst A.
N CI
[322] Yellow solid (0.416 g, 81%) ; 1H NMR
(400 MHz, MeOD) 5 8.69 (dt, J = 5.2, 1.3 Hz, 1H), 7.88 (td,
J = 7.9,1.5 Hz, 1H), 7.46-7.31 (m, 2H), 1.67 (s, 15H), 1.46
3 (s, 6H); 1 C NMR (150 MHz, MeOD) 5 177.34, 150.97, 139.53,
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125.54, 122.95, 85.97,84.74, 33.67, 9.01.
[323] [Comparative Example 2] Preparation of metal complex
B DCM
[IrCp*Cl21 2 + | + Na 2CO 3 -"I Ci No rt,12h O
[324] OH
[325] [IrCp*Cl 2 ]2 (0.20 g, 0.25 mmol), quinolin-8-ol (72.6
mg, 0.50 mmol), sodium carbonate (0.21 g, 2.0 mmol), and
acetone (10 mL) were added to a vial and the mixture was
stirred at room temperature for 12 hours. After the
reaction was completed, the reactants were filtered with
celite (dichloromethane (15 mLx3)), the solvent was removed
by distillation under reduced pressure, and separation and
purification were performed by column chromatography (n
hexane/acetone = 2:1 to 1:1) to prepare metal catalyst B.
[326] 8-Hydroxyquinoline bound Cp*-iridium complex (metal
catalyst B)
N' CI
[327] Orange solid (0.20 g, 80%); 1H NMR
(600 MHz, CDCl3 ) 5 8.54 (d, J = 4.9 Hz, 1H), 8.03 (d, J =
8.3 Hz, 1H), 7.36 (t, J = 7.9 Hz, 1H), 7.30 (dd, J = 8.3,
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4.9 Hz, 1H), 7.00 (d, J = 7.9 Hz, 1H), 6.78 (d, J = 7.9 Hz, 3 1H), 1.73 (s, 15H); 1 C NMR (150 MHz, CDCl3 ) 5 169.1, 146.0,
145.8, 137.7, 131.0, 130.7, 121.9, 115.6, 110.9, 84.8 (Cp*),
8.9 (Cp*); IR (cm-1) 1564, 1455, 1367, 1320, 1111, 826, 751,
512; HRMS (EI) m/z calcd. for Ci 9H 21ClIrNO [M]+: 507.0941,
found: 507.0943.
[328] Preparation Example II: Preparation of carboxylic
acid compound
[329] [Preparation Example 6] Preparation of 2-ethylbenzoic
acid
Br n-BuLi/THF C02 (balloon) C0 2H
[ -78 °C, 30 min 1 h rt, 20 min |
[330]
[331] 1-bromo-2-ethylbenzene (1.38 ml, 10 mmol) was
dissolved in THF (30mL), and n-BuLi (2.5 M in hexane, 6.0
ml, 15 mmol) was slowly added thereto at -78°C. Thereafter,
the mixture was stirred at the same temperature for 30
minutes and then anhydrous CO 2 was bubbled for 1 hour. The
temperature of the reaction mixture was raised again, and
the mixture was stirred at room temperature for 20 minutes,
quenched with a saturated aqueous NaHCO 3 solution, and
washed with Et 2 0. An aqueous solution layer was acidified
with a 1 N aqueous HCl solution, and then extracted with
Et 2 0. The extracted solution was dried and concentrated to
obtain 2-ethylbenzoic acid as a white solid (0.77 g, 50%).
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[332] [Preparation Example 7] Preparation of (S)-2-(1,3
dioxoisoindolin-2-yl)-4-methylpentanoic acid and (S)-2
(1,3-dioxoisoindolin-2-yl)-4-phenylbutanoic acid
O
Reflux RyKOH RY OH + | + NEt 3 Toluene O N 0 NH 2
[333]
[334] a-Amino acid (20 mmol), phthalic anhydride (3.0 g, 20
mmol), and triethylamine (Et 3N, 0.28 mL, 2 mmol) were added
to toluene (20 mL). The reaction mixture was heated at
130°C for 4 hours, and moisture produced during the
reaction was collected by a water separator. The reaction
mixture was cooled to room temperature, the solvent was
removed under reduced pressure, and the reactants were
dissolved in DCM (150 mL) and washed twice with an aqueous
HCl solution (0.5-1.0 M, 100 mL) and three times with a
saline (100 mL). The collected organic layer was dried
with anhydrous MgSO4, filtered with celite using DCM (30
mL), and distilled under reduced pressure to prepare a
carboxylic acid protected by phthalimido with a yield of
% or more.
[335] [Preparation Example 8] Preparation of (R)-3-(1,3
dioxoisoindolin-2-yl)-4-methylpentanoic acid
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TFA/DCM OCOCF 3 Phthalic anhydride/NEt 3 2 CO 2 H CO 2 H o N O BocNH 1h NH 3+ THF, reflux
[33 6]
[337] A mixed solution of Boc-p-leucine (0.75 g, 3.3 mmol)
and trifluoroacetic acid/dichloromethane (TFA/DCM, 10 mL,
1:1) was added to a round flask and the solution was
stirred for 1 hour. The reaction mixture was concentrated
under reduced pressure to remove TFA, and the residue was
triturated with toluene (3 mL) and then concentrated. A P
alanine TFA salt was dissolved in THF (15 mL), Et3N (0.66 g,
6.5 mmol) and phthalic anhydride (0.49 g, 3.3 mmol) were
added thereto, and the reactants were heated to reflux
overnight under an argon atmosphere. The reaction mixture
was cooled to room temperature and concentrated under
vacuum, and the residue was diluted with 1 N HCl (10 mL)
and extracted with EtOAc (60 mL). The extracted organic
layer was washed with a saline, dried with Na2SO4, and
concentrated. The concentrated residue was separated and
purified with column chromatography (DCM/MeOH, 9:1) to
obtain (R)-3-(1,3-dioxoisoindolin-2-yl)-4-methylpentanoic
acid as a colorless oil (0.40 g, 47%).
[338] A carboxylic acid compound other than the carboxylic
acid prepared by the above method was purchased from
Aldrich, Alfa, TCI, or the like and used without separate
purification.
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[339] Preparation Example III: Preparation of hydroxamic
acid compound
[340] Method A. One-pot synthesis of hydroxamic acids from
carboxylic acids
O OMe in-situ generated 0
R C1AO-' +(N + COHI Diethyl ether NH 2OH in MeOH R NOH 0 0°C,10 min rt,1 h H
[341]
[342] Preparation of in-situ generated hydroxylamine: A
solution of hydroxylamine hydrochloride (1.0 g, 15 mmol)
dissolved in methanol (10 mL) at 0°C was added to a
solution of potassium hydroxide (0.84 g, 15 mmol) dissolved
in methanol (4 mL) and then the solution was stirred at the
same temperature for 15 minutes. Precipitated potassium
chloride was removed, and then the produced filtrate was
used in the next reaction without purification.
[343] A carboxylilc acid compound (10 mmol) was dissolved
in diethyl ether (30 mL), ethylchloroformate (1.3 g, 12
mmol) and N-methylmorpholine (1.3 g, 13 mmol) were added
thereto at 0°C, and then the reaction mixture was stirred
for 10 minutes. After removing a solid by filtration, the
filtrate was added to a hydroxylamine (0.5 g, 15 mmol)
solution dissolved in methanol (in-situ generated
hydroxylamine) and the solution was stirred at room
temperature for 15 minutes to proceed with the reaction.
The solvent was removed, and the residue was separated and
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purified by column chromatography (eluent: n-hexane/EtOAc,
1:1 to 1:5) to obtain the desired hydroxamic acid compound.
[344] Method B. One-pot synthesis of hydroxamic acids from
carboxylic acids
O CDI NH 2 OH-HCI 0 Rt N.OH
[345] R OH THF, rt, 1 h 16h H
[346] A carboxylic acid compound (10 mmol) was added to
dried tetrahydrofuran (THF, 30 mL), 1,1'
Carbonyldiimidazole (CDI, 15 mmol, 1.5 equiv) was added
thereto, and the mixture was stirred for 1 hour.
Hydroxylamine hydrochloride (1.39 g, 20 mmol) in a powder
form was added and the mixture was stirred for 16 hours.
After the reaction was completed, the reaction mixture was
added to a 5% aqueous KHSO 4 solution (30 mL), and extracted
with EtOAc (2 x 30 mL). The collected organic layer was
washed with a saline (50 mL), dried with MgSO4,
concentrated, and separated and purified by column
chromatography (eluent: n-hexane/EtOAc, 1:1 to 1:5) to
obtain the desired hydroxamic acid compound.
[347] Method C. Synthesis of hydroxamic acids from ester
NH 2 OH-HCI (3 equiv) 0 O M KOH (6 equiv) R ,OH A ,Me R N MeOH, reflux, overnight H
[348] R 0
[349] A methyl ester compound (10.0 mmol) and hydroxylamine
hydrochloride (2.08 g, 30 mmol, 3.0 equiv) were dissolved
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in methanol (50 mL). Solid hydroxylamine hydrochloride
(3.37 g, 60 mmol, 6.0 equiv) was added thereto and heated
to reflux for 24 hours. 1 N HCl was added to the reaction
mixture to adjust pH to 4 and concentrated to remove
methanol. Water (50 mL) was added to the residue and
extracted with EtOAc (3 x 50 mL). The collected organic
layer was dried with MgSO4 and concentrated, and then
separated and purified with column chromatography (eluent:
n-hexane/EtOAc, 1:1 to 1:5) to obtain the desired
hydroxamic acid compound.
[350] Method D. One-pot synthesis of hydroxamic acids from
carboxylic acids
1. Oxalyl Chloride OH DMF (cat.), DCM, O0 C to rt 0 R OH 2. NH 2 OH-HCI, K 2 CO 3 R NHOH
[351] EtOAc/H 2 0 (2:1), 0 oC to rt
[352] A carboxylic acid compound (2.0 mmol) was dissolved
in dichloromethane (30 mL), and then oxalyl chloride (4.0
mmol) and DMF (2 drops) were added at 0°C. This mixture
was stirred at room temperature for 2.5 to 4 hours. After
the solvent was removed under reduced pressure, the residue
was directly used in the next reaction without purification.
[353] Hydroxylamine hydrochloride (1.2 equiv) and K2 CO 3 (2.0
equiv) were dissolved in a solvent in which water (8 mL)
and EtOAc (16 mL) were mixed at 1:2, and then cooled to 0°C.
In this solution, the acid chloride prepared above
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dissolved in a minimal amount of ethyl acetate was
dissolved and then the reaction mixture was stirred at room
temperature for 12 hours. An organic layer and an aqueous
solution layer were separated, and then the aqueous
solution layer was extracted with EA. The collected
organic layer was dried with anhydrous MgSO 4 , concentrated,
and separated and purified by column chromatography
(eluent: DCM/ methanol = 30:1 to 10:1) to obtain the
desired hydroxamic acid compound.
[354] [Preparation Example 9] Preparation of 4
phenylbutanyl hydroxamic acid
0 NOH H
[355] Prepared from 4-phenylbutyric
acid (2 mmol scale) by Method B; White solid (0.34 g, 95%);
1H NMR (600 MHz, CDCl 3 ) 5 8.50 (br, 2H), 7.28-7.24 (m, 2H),
7.18 (t, J = 7.4 Hz, 1H), 7.14 (d, J = 7.4 Hz, 2H), 2.61 (t,
J = 7.6 Hz, 2H), 2.11 (t, J = 7.6 Hz, 2H), 1.94 (p, J = 7.5
3 Hz, 2H); 1 C NMR (150 MHz, CDCl 3 ) 5 171.4, 140.9, 128.4,
128.4, 126.1, 34.9, 32.1, 26.7.
[356] [Preparation Example 10] Preparation of 4-(4
bromophenyl)butanyl hydroxamic acid
Br
NOH H
[357] Prepared from 4-(4
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bromophenyl)butyric acid (2.0 mmol scale) by Method B;
solid (0.50, 96%); m.p. 99-101°C; 1H NMR (600 MHz, CDCl 3 ) 5
8.15 (s, 2H), 7.40 (d, J = 7.9 Hz, 2H), 7.03 (d, J = 7.9 Hz,
2H), 2.59 (t, J = 7.6 Hz, 2H), 2.13 (t, J = 7.5 Hz, 2H),
1.95 (p, J = 7.5 Hz, 2H); 13C NMR (150 MHz, CDCl 3 ) 5 170.8,
139.8, 131.5, 130.1, 119.9, 34.2, 31.8, 26.4; IR (cm-1)
3206, 3037, 2896, 1623, 1486, 1071, 1009; HRMS (EI) m/z
calcd. for CioH1 2 BrNO 2 [M]+: 257.0051, found: 257.0049.
[358] [Preparation Example 11] Preparation of 4-(4
fluorophenyl)butanyl hydroxamic acid
F N'OH H
[359] Prepared from 4-(4
fluorophenyl)butyric acid (5 mmol scale) by Method B: White
solid (0.71 g, 72%); m.p. 48-50°C; 'H NMR (600 MHz,
acetone-d6) 5 9.98 (s, 1H), 8.24 (s, 1H), 7.27-7.17 (m, 2H),
7.01 (t, J= 8.8 Hz, 2H), 2.60 (t, J = 7.6 Hz, 2H), 2.11 (t,
J = 7.5 Hz, 2H), 1.88 (p, J = 7.5 Hz, 2H); 13 C NMR (150 MHz,
acetone-d6) 5 170.3, 161.2 (d, J = 241.4 Hz), 137.8, 130.0
(d, J = 8.0 Hz), 114.8 (d, J = 21.1 Hz), 33.9, 31.6, 27.2;
1 9F NMR (564 MHz, acetone-d6) 5 -119.2 (m) ; IR (cm-1) 3167,
2907, 1607, 1507, 1222, 1068, 820; HRMS (EI) m/z calcd. for
CioH12FNO2 [M]+: 197.0852, found: 197.0850.
[360] [Preparation Example 12] Preparation of 4-(4
nitrophenyl)butanyl hydroxamic acid
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0 2N
2N N'OH H
[361] Prepared from 4-(4
nitrophenyl)butyric acid (2.0 mmol scale) by Method B:
White solid (0.43 g, 95%); m.p. 109-111°C; 1H NMR (600 MHz,
DMSO-d) 5 10.33 (s, 1H), 8.66 (s, 1H), 8.13 (d, J = 8.7 Hz,
2H), 7.45 (d, J = 8.4 Hz, 2H), 2.67 (t, J = 7.8 Hz, 2H),
1.95 (t, J = 7.4 Hz, 2H), 1.80 (q, J = 7.6 Hz, 2H); 1 3 C NMR
(150 MHz, DMSO-d) 5 169.0, 150.6, 146.3, 130.1, 123.9,
34.7, 32.0, 26.8; IR (cm-1) 3187, 3037, 2902, 1628, 1510,
1346, 849; HRMS (EI) m/z calcd. for CioH1 2 N2 0 4 [M]+: 224.0797,
found: 224.0795.
[362] [Preparation Example 13] Preparation of 4-(4
methoxyphenyl)butanyl hydroxamic acid
MeO O NOH H
[363] Prepared from 4-(4
methoxyphenyl)butyric acid (2.0 mmol scale) by Method B;
White solid (0.41 g, 97%); m.p. 97-99°C; 1H NMR (600 MHz,
CDCl 3 ) 5 8.56 (br, 1H), 8.25 (s, 1H), 7.06 (d, J = 8.5 Hz,
2H), 6.82 (d, J = 8.7 Hz, 2H), 3.78 (s, 3H), 2.57 (t, J =
7.5 Hz, 2H), 2.11 (t, J = 7.3 Hz, 2H), 1.94 (q, J = 7.6 Hz,
2H); 13 C NMR (150 MHz, CDCl3) 5 171.3, 157.9, 132.9, 129.3,
113.9, 55.2, 33.9, 32.0, 26.8; IR (cm-1) 3216, 3034, 2900,
1609, 1509, 1241, 1028; HRMS (EI) m/z calcd. for CiiHi 5NO3
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[M]+: 209.1052, found: 209.1052.
[364] [Preparation Example 14] Preparation of tert-butyl
[4-{4-(hydroxyamino)-4-oxobutyliphenyl]carbamate
H
01NNHOH
[365] - Prepared by Method A (2.0 mmol scale); White solid (0.44 g, 78%); m.p. 120
122 0 C; 'H NMR (400 MHz, CDCl,) 5 10.32 (s, 1H), 9.20 (s,
1H), 8.66 (s, 1H), 7.30 (d, J = 8.1 Hz, 2H), 7.00 (d, J =
8.5 Hz, 2H), 2.40 (t, J = 7.6 Hz, 2H), 1.89 (t, J = 7.4 Hz,
2H) , 1. 69 (p, J = 7.8 Hz, 2H) , 1. 42 (s, 9H) ; 13 C NMR (150
MHz, CDCl,) 5 169.3, 153.3, 137.7, 135.6, 128.8, 118.7,
79.2, 34.4, 32.2, 28.6, 27.5; IR (cm-1) 3343, 3286, 1695,
1624, 1523, 1239, 1162; HRMS (FAB) m/z calcd. for Ci 5 H2 2 N 2 04
[M+H]+: 295.1658, found: 295.1661.
[366] [Preparation Example 15] Preparation of 2,2-dimethyl
4-phenylbutanyl hydroxamic acid
0 NOH H
[367] Prepared from 2,2-dimethyl-4
phenylbutanoic acid by Method D; White solid (0.89 g, 93%);
m.p. 131-133°C; 1H NMR (600 MHz, CDCl3 ) 5 8.42 (br, 2H),
7.28-7.24 (m, 3H), 7.16 (dd, J= 19.0, 7.4 Hz, 3H), 2.56
3 2.49 (m, 2H), 1.87-1.80 (m, 2H), 1.24 (s, 6H); 1 C NMR (150
MHz, CDCl3) 5 175.5, 141.7, 128.4, 128.3, 125.9, 42.8, 40.1,
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31.2, 24.6; IR (cm-1) 3250, 2920, 1606, 1516, 1492, 697;
HRMS (EI) m/z calcd. for C1 2Hi 7 NO 2 [M]+: 207.1259, found:
207.1261.
[368] [Preparation Example 16] Preparation of 2-methyl-4
phenylbutanyl hydroxamic acid
0 , OH H
[369] Prepared from 2-methyl-4
phenylbutanoic acid by Method D: White solid (0.34 g, 88%);
m.p. 126-128°C; 'H NMR (400 MHz, acetone-d6) 5 10.09 (s,
1H), 8.42 (s, 1H), 7.25-7.20 (m, 2H), 7.18-7.08 (m, 3H),
2.60-2.46 (m, 2H), 2.31-2.19 (m, 1H), 1.96-1.83 (m, 1H),
3 1.72-1.53 (m, 1H), 1.08 (d, J = 6.9 Hz, 3H); 1 C NMR (151
MHz, acetone-d6, one carbon merged to others) 5 173.4, 142.0,
128.2, 125.7, 37.0, 35.7, 33.3, 17.4; IR (cm-1) 3201, 3027,
2918, 1620, 1453, 1033, 697; HRMS (EI) m/z calcd. for
CiiHi 5 NO2 [M]+: 193.1103, found: 193.1103.
[370] [Preparation Example 17] Preparation of 3-methyl-4
phenylbutanyl hydroxamic acid
- 0
N'OH H
[371] Prepared from 3-methyl-4
phenylbutanoic acid by Method B; White solid (1.24g, 68%);
m.p. 75-77°C; 1H NMR (600 MHz, CDCl,) 6 8.53 (br, 2H), 7.26
(t, J = 7.2 Hz, 2H), 7.19 (t, J = 7.2 Hz, 1H), 7.12 (d, J=
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7.2 Hz, 2H), 2.59 (dd, J = 13.2, 6.5 Hz, 1H), 2.47 (dd, J=
13.1, 7.8 Hz, 1H), 2.30-2.23 (m, 1H), 2.14 (dd, J = 14.1,
4.9 Hz, 1H), 1.90-1.84 (m, 1H), 0.90 (d, J = 6.4 Hz, 3H);
3 1 C NMR (150 MHz, CDC1 3 ) 5 170.8, 139.9, 129.1, 128.3, 126.1,
43.0, 39.6, 32.4, 19.3; IR (cm-1) 3208, 2920, 1632, 1453,
1030, 698; HRMS (EI) m/z calcd. for C11Hi 5 NO 2 [M]+: 193.1103,
found: 193.1100.
[372] [Preparation Example 18] Preparation of 2-(2,3
dihydro-1H-inden-2-yl)acetyl hydroxamic acid
00"JN..OH H
[373] 1 Prepared from 2-indanylacetic acid by Method A: White solid (0.34g, 89%); m.p. 142-144°C; 1H
NMR (600 MHz, DMSO-d 6 ) 5 10.36 (s, 1H), 8.70 (s, 1H), 7.19
7.15 (m, 2H), 7.10-7.06 (m, 2H), 2.97 (dd, J = 15.7, 7.8 Hz,
2H), 2.71 (dt, J = 14.9, 7.3 Hz, 1H), 2.55 (dd, J= 15.6,
6.7 Hz, 2H), 2.08 (d, J = 7.5 Hz, 2H); 13 C NMR (150 MHz,
DMSO-d6) 5 168.7, 143.0, 126.6, 124.8, 38.8, 38.4, 36.6; IR
(cm-1) 3279, 2936, 1623, 1470, 974, 742; HRMS (EI) m/z
calcd. for C11H13NO 2 [M]+: 191.0946, found: 191.0944.
[374] [Preparation Example 19] Preparation of 2-ethylbenzyl
hydroxamic acid
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0 'OH OH | H
[375] Prepared from 2-ethylbenzoic acid by
Method D; White solid (0.29g, 86%); m.p. 114-116°C; 'H NMR
(600 MHz, CDCl 3 ) o 8.77 (br, 2H), 7.37 (t, J = 7.5 Hz, 1H),
7.26 (t, J = 8.5 Hz, 2H), 7.16 (t, J = 7.5 Hz, 1H), 2.74 (q,
J = 7.5 Hz, 2H), 1.18 (t, J = 7.5 Hz, 3H); 13C NMR (150 MHz,
CDCl 3 ) 5 168.9, 143.2, 131.4, 130.9, 129.5, 127.3, 125.8,
26.1, 15.7; IR (cm-1) 3186, 2969, 2873, 1617, 1517, 1018,
901; HRMS (EI) m/z calcd. for C 9 HiiNO 2 [M]+: 165.0790,
found: 165.0789.
[376] [Preparation Example 20] Preparation of 2
benzylbenzyl hydroxamic acid
0 N'OH | H
[377] Prepared from 2-benzylbenzoic acid by
Method D; White solid (0.41g, 39%); m.p. 146-148°C; 'H NMR
(600 MHz, DMSO-d) 5 10.90 (s, 1H), 9.06 (s, 1H), 7.31 (t,
J = 7.5 Hz, 1H), 7.26-7.20 (m, 6H), 7.15 (dd, J = 12.7, 7.3
Hz, 2H), 4.04 (s, 2H); 13C NMR (150 MHz, DMSO-d6) 5 166.1,
140.9, 139.4, 134.4, 130.1, 129.7, 128.9, 128.3, 127.5,
125.9, 125.8, 37.5; IR (cm-1) 3243, 2864, 1613, 1450, 743,
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701; HRMS (EI) m/z calcd. for Ci 4Hi3N0 2 [M]+: 227.0946,
found: 277.0949.
[378] [Preparation Example 21] Preparation of 4
(benzofuran-2-yl)butanyl hydroxamic acid
1 N'OH H
[379] Prepared from methyl 4
(benzofuran-2-yl)butanoate by Method C; White solid (1.72 g,
78%); m.p.101-103 0 C; 1H NMR (400 MHz, CDCl 3 ) 5 8.24 (s, 2H),
7.47 (d, J = 7.5 Hz, 1H), 7.40 (d, J = 8.1 Hz, 1H), 7.20
(dt, J= 20.9, 7.6 Hz, 2H), 6.41 (s, 1H), 2.82 (t, J = 7.0
Hz, 2H), 2.22 (t, J = 7.0 Hz, 2H), 2.11 (p, J = 7.1 Hz,
3 2H); 1 C NMR (150 MHz, CDCl 3 ) 5 193.2, 157.7, 154.7, 128.6,
123.4, 122.6, 120.3, 110.8, 102.8, 31.7, 27.4, 23.3; IR
(cm-1) 3163, 2999, 2890, 1624, 1452, 747, 619; HRMS (EI)
m/z calcd. for Ci 2 Hi3NO3 [M]+: 219.0895, found: 219.0897.
[380] [Preparation Example 22] Preparation of 4-(thiophen
2-yl)butanyl hydroxamic acid
-- L ~ N'OH H
[381] Prepared from 4-(thiophen-2
yl)butanoic acid by Method B; White solid (1.64 g, 88%);
m.p. 69-71°C; 'H NMR (400 MHz, CDCl3) 5 8.76 (br, 2H), 7.11
(dd, J = 5.1, 1.0 Hz, 1H), 6.90 (dd, J = 5.1, 3.4 Hz, 1H),
6.77 (d, J = 2.6 Hz, 1H), 2.84 (t, J = 7.3 Hz, 2H), 2.16 (t,
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J= 7.3 Hz, 2H), 2.00 (p, J= 7.5 Hz, 2H); 13C NMR (150 MHz,
CDCl 3 ) 5 171.2, 143.6, 126.8, 124.7, 123.4, 31.8, 28.9,
27.0; IR (cm-1) 3218, 3034, 2898, 1621, 1528, 1071, 704;
HRMS (EI) m/z calcd. for CsHiiNO 2 S [M]+: 185.0510, found:
185.0513.
[382] [Preparation Example 23] Preparation of 4
methylpentanyl hydroxamiclll acid
0 N'OH H
[383] Prepared from 4-methylpentanoic acid
by Method B; White solid (1.26 g, 96%); m.p. 47-49°C; 'H
NMR (600 MHz, CDCl 3 ) 5 9.18 (br, 2H), 2.14 (t, J= 7.8 Hz,
2H) , 1. 61-1. 47 (m, 3H) , 0.88 (d, J = 6. 4 Hz, 6H); 13 C NMR
(150 MHz, CDCl3 ) 5 172.2, 34.2, 31.0, 27.7, 22.2; IR (cm-1)
3186, 2954, 2922, 1625, 1533, 1057, 586; HRMS (EI) m/z
calcd. for C 6Hi 3 NO 2 [M]+: 131.0946, found: 131.0948.
[384] [Preparation Example 24] Preparation of 3
cyclohexylpropanyl hydroxamic acid
0
NOH H
[385] Prepared from 3-cyclohexylpropanoic
acid by Method B; White solid (1.63 g, 95%); m.p. 81-83°C;
'H NMR (600 MHz, CDCl3) 5 8.78 (br, 2H), 2.15 (t, J = 8.3
Hz, 2H), 1.72-1.62 (m, 5H), 1.51 (q, J = 7.1 Hz, 2H), 1.24
3 1.11 (m, 4H), 0.88 (q, J = 14.4, 12.6 Hz, 2H); 1 C NMR (150
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MHz, CDCl 3 ) 5 172.2, 37.2, 32.9, 32.7, 30.6, 26.5, 26.2; IR
(cm-1) 3254, 2925, 2848, 1619, 1447, 736; HRMS (EI) m/z
calcd. for C9Hi 7 NO2 [M]+: 171.1259, found: 171.1261.
[386] [Preparation Example 25] Preparation of 2
isopropylbenzyl hydroxamic acid
0
| H
[387] Prepared from 2-isopropylbenzoic acid
by Method D; White solid (0.32 g, 88%); m.p. 89-91°C; 'H
NMR (600 MHz, CDCl3) 5 8.60 (br, 2H), 7.43 (t, J= 7.5 Hz,
1H), 7.39 (d, J = 7.8 Hz, 1H), 7.27 (d, J = 4.5 Hz, 1H),
7.19 (t, J = 7.4 Hz, 1H), 3.27 (p, J = 6.8 Hz, 1H), 1.23 (d,
3 J = 6.8 Hz, 6H); 1 C NMR (150 MHz, CDCl 3 ) 5 169.0, 147.8,
131.1, 131.0, 127.2, 126.3, 125.8, 30.0, 24.1; IR (cm-1)
3198, 2965, 1743, 1629, 1597, 1022, 761; HRMS (EI) m/z
calcd. for CioHi3NO2 [M]+: 179.0946, found: 179.0947.
[388] [Preparation Example 26] Preparation of pentanyl
hydroxamic acid
0 OH H
[389] Prepared from pentanoic acid (5 mmol
scale) by Method B; White solid (0.44g, 75%); m.p. 52-54°C;
1H NMR (600 MHz, CDCl3 ) 5 8.76 (s, 2H), 2.15 (t, J = 7.6 Hz,
2H), 1.61 (p, J = 7.7 Hz, 2H), 1.34 (q, J = 7.3 Hz, 2H),
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0.90 (t, J = 7.3 Hz, 3H); 13C NMR (150 MHz, CDCl 3 ) 5 171.9,
32.7, 27.4, 22.2, 13.6; IR (cm-1) 3204, 2930, 1626, 1457,
1039; HRMS (EI) m/z calcd. for C 5 HiiNO2 [M]+: 117.0790,
found: 117.0788.
[390] [Preparation Example 27] Preparation of 2
cyclopentylacetyl hydroxamic acid
j N' OH H
[391] Prepared from 2-cyclopentylacetic
acid (5 mmol scale) by Method B; White solid (1.33g, 93%);
m.p. 113-115°C; 1H NMR (600 MHz, DMSO-d) 5 10.28 (s, 1H),
8.63 (s, 1H), 2.10 (hept, J = 7.6 Hz, 1H), 1.91 (d, J = 7.5
Hz, 2H), 1.69-1.63 (m, 2H), 1.53 (tq, J = 10.6, 6.0, 4.3 Hz,
2H), 1.47 (ddd, J = 11.6, 9.7, 7.2 Hz, 2H), 1.08 (dq, J =
3 15.6, 7.8 Hz, 2H); 1 C NMR (150 MHz, DMSO-d 6 ) 5 169.1, 38.8,
36.9, 32.3, 24.9; IR (cm-1) 3171, 2950, 2864, 1625, 1448,
981, 534; HRMS (EI) m/z calcd. for C 7H13NO2 [M]+: 143.0946,
found: 143.0945.
[392] [Preparation Example 28] Preparation of 2-(adamantan
1-yl)acetyl hydroxamic acid
O N'OH H
[393] Prepared from 1-adamantaneacetic acid by
Method D; White solid (0.34g, 80%); m.p. 179-181°C; 'H NMR
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(600 MHz, DMSO-d) 5 10.21 (s, 1H), 8.60 (s, 1H), 1.89 (s,
3H), 1.67 (s, 2H), 1.63 (d, J = 11.9 Hz, 3H), 1.55-1.52 (m,
3 9H); 1 C NMR (150 MHz, DMSO-d6) 5 167.2, 47.1, 42.5, 36.9,
32.6, 28.5; IR (cm-1) 3199, 2897, 2842, 1622, 1536, 1068;
HRMS (EI) m/z calcd. for Ci 2 H1 9 NO 2 [M]+: 209.1416, found:
209.1415.
[394] [Preparation Example 29] Preparation of hex-5-enyl
hydroxamic acid
0
N'OH H
[395] Prepared from methyl hex-5
enoate(15 mmol scale) by Method C; Yellowish oil (1.54g,
%); 1H NMR (400 MHz, CDCl 3 ) 5 9.24 (s, 2H), 5.74 (td, J =
16.8, 6.7 Hz, 1H), 5.05-4.95 (m, 2H), 2.14 (t, J = 7.6 Hz,
2H), 2.06 (q, J = 7.2 Hz, 2H), 1.71 (p, J = 7.5 Hz, 2H);
3 1 C NMR (150 MHz, CDCl,) 5 171.8, 137.4, 115.6, 32.9, 32.1,
24.4; IR (cm-1) 3197, 2903, 1628, 911; HRMS (EI) m/z calcd.
for C6HiiNO2 [M]+: 129.0790, found: 129.0791.
[396] [Preparation Example 30] Preparation of (E)-6
Phenylhex-5-enyl hydroxamic acid
NOH H
[397] Prepared from methyl (E)-6
phenylhex-5-enoate (6.4 mmol scale) by Method C; White
solid (0.80g, 61%); m.p. 100-102°C; 'H NMR (600 MHz, DMSO
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d6 ) 5 10.33 (s, 1H), 8.65 (s, 1H), 7.36 (d, J = 7.7 Hz, 2H),
7.27 (t, J = 7.5 Hz, 2H), 7.17 (t, J = 7.4 Hz, 1H), 6.36 (d,
J = 15.9 Hz, 1H), 6.25 (dt, J = 15.2, 6.8 Hz, 1H), 2.13 (q,
J = 7.3 Hz, 2H), 1.97 (t, J = 7.5 Hz, 2H), 1.63 (p, J = 7.5
3 Hz, 2H); 1 C NMR (150 MHz, DMSO-d) 5 169.3, 137.7, 130.5,
130.4, 128.9, 127.4, 126.3, 32.3, 32.2, 25.3; IR (cm-1)
3174, 3020, 2922, 1625, 964, 689; HRMS (EI) m/z calcd. for
C1 2 Hi 5 NO 2 [M]+: 205.1103, found: 205.1104.
[398] [Preparation Example 31] Preparation of 5-phenylhex
-enyl hydroxamic acid
N'OH H
[399] Prepared from methyl 5-phenylhex
-enoate(3.5 mmol scale) by Method C; White solid(0.57g,
79%); m.p. 77-79°C; 1H NMR (400 MHz, CDCl 3 , two protons
can't detected due to broadness) 5 7.37 (d, J = 7.6 Hz, 2H),
7.32 (t, J = 6.9 Hz, 2H), 7.30-7.25 (m, 1H), 5.30 (s, 1H),
5.07 (s, 1H), 2.54 (t, J = 7.2 Hz, 2H), 2.14 (t, J = 6.8 Hz,
2H), 1.80 (p, J = 7.3 Hz, 2H); 13 C NMR (150 MHz, CDCl 3 ) 5
171.0, 147.3, 140.6, 128.4, 127.6, 126.1, 113.2, 34.4, 32.0,
23.5; IR (cm-1) 3172, 3024, 2909, 1624, 1450, 904, 777,
707; HRMS (EI) m/z calcd. for C12Hi 5 NO2 [M]+: 205.1103,
found: 205.1100.
[400] [Preparation Example 32] Preparation of 6-phenylhex
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-ynyl hydroxamic acid
N* .OH N H
[401] Prepared from methyl 6
phenylhex-5-ynoate by Method C; White solid (1. 9g, 93%) ;
m.p. 66-68°C; 1H NMR (400 MHz, CDCl 3 ) 5 8.66 (s, 2H), 7.39
7.34 (m, 2H), 7.28-7.23 (m, 3H), 2.45 (t, J = 6.8 Hz, 2H),
2.32 (t, J = 7.4 Hz, 2H), 1.92 (p, J = 7.2 Hz, 2H); 13C NMR
(150 MHz, CDCl3) 5 171.1, 131.5, 128.2, 127.8, 123.5, 88.4,
81.8, 31.6, 24.2, 18.7; IR (cm-1) 3269, 3200, 2903, 1624,
1438, 1035, 752, 689; HRMS (EI) m/z calcd. for C1 2 H1 3 NO 2
[M]+: 203.0946, found: 203.0945.
[402] [Preparation Example 33] Preparation of 7-phenylhept
-ynyl hydroxamic acid
0 I K' OH H
[403] Prepared from methyl 7
phenylhept-5-ynoic acid (2 mmol scale) by Method B; Yellow
resin (0.33 g, 75%); 'H NMR (600 MHz, acetone-d6) 5 10.36
(s, 1H), 9.29 (s, 1H), 7.35-7.33 (m, 2H), 7.29 (t, J = 7.6
Hz, 2H), 7.20 (t, J = 7.3 Hz, 1H), 3.56 (s, 2H), 2.32-2.22
(m, 4H), 1.82 (p, J = 7.3 Hz, 2H); 13 C NMR (150 MHz,
acetone-d6) 5 170.5, 137.6, 128.4, 127.8, 126.3, 81.4, 78.4,
31.5, 25.0, 24.5, 18.0; IR (cm-1) 3196, 2934, 1638, 1451,
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1264, 766, 694; HRMS (ESI) m/z calcd. for C1 3 Hi 5NO 2 [M+H]+:
218.1176, found: 218.1157.
[404] [Preparation Example 34] Preparation of hept-5-ynyl
hydroxamic acid
0 NOH H
[405] Prepared from hept-5-ynoic acid
by Method B; White solid (1.45 g, 62%); m.p. 74-76°C; 1H
NMR (600 MHz, acetone-d6) 5 10.07 (s, 1H), 8.78 (s, 1H),
2.19 (t, J = 7.3 Hz, 2H), 2.14-2.10 (m, 2H), 1.76-1.66 (m,
3 H); 1 C NMR (150 MHz, acetone-d6) 5 169.8, 77.9, 75.7, 31.2,
24.9, 17.8, 2.3; IR (cm-1) 3255, 3060, 2740, 1657, 1433,
1021, 444; HRMS (EI) m/z calcd. for C7 HiiNO 2 [M]+: 141.0790,
found: 141.0790.
[406] [Preparation Example 35] Preparation of 3
benzylpentanyl hydroxamic acid
0 NOH H
[407] Prepared from 3-benzylpentanoic
acid (1.5 mmol scale) by Method D; White solid (0.28 g,
89%); m.p. 90-92°C; 1H NMR (400 MHz, CDCl 3 , two protons
can't detected due to broadness) 5 7.29 (t, J = 7.3 Hz, 2H),
7.20 (t, J = 7.3 Hz, 1H), 7.15 (d, J = 7.5 Hz, 2H), 2.68
(dd J = 13.6, 6.6 Hz, 1H), 2.51 (dd, J = 13.6, 7.3 Hz, 1H),
2.25-2.09 (m, 1H), 2.04 (d, J = 6.7 Hz, 2H), 1.37 (p, J=
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7.4 Hz, 2H), 0.92 (t, J = 7.3 Hz, 3H); 13 C NMR (150 MHz,
CDCl 3 ) 5 171.2, 140.0, 129.2, 128.3, 126.1, 39.6, 38.5,
36.6, 25.9, 10.9; IR (cm-1) 3223, 2961, 2928, 1636, 1494,
1453, 699; HRMS (FAB) m/z calcd. for C1 2 Hi7 NO 2 [M+H]+
208.1338, found: 208.1338.
[408] [Preparation Example 36] Preparation of 3-benzyl-4
methylpentanyl hydroxamic acid
N'OH N H
[409] Prepared from 3-benzyl-4
methylpentanoic acid (1.8 mmol scale) by Method D; Yellow
solid (0.34 g, 82%); m.p. 80-82°C; 1H NMR (400 MHz, CD 2 Cl 2
) 8.97 (s, 2H), 7.29 (t, J = 7.2 Hz, 2H), 7.24-7.14 (m, 3H),
2.64 (dd, J = 13.1, 6.0 Hz, 1H), 2.45 (dd, J = 12.4, 6.8 Hz,
1H), 2.19-2.02 (m, 2H), 1.98-1.86 (m, 1H), 1.78-1.65 (m,
1H), 0.89 (dd, J = 14.3, 6.5 Hz, 6H); 13 C NMR (100 MHz,
CD2Cl2) 5 172.0, 141.1, 129.4, 128.5, 126.1, 43.1, 36.8,
33.7, 28.6, 18.9, 18.3; IR (cm-1) 3205, 2956, 1635, 698;
HRMS (FAB) m/z calcd. for C13H1 9 NO 2 [M+H]+ : 222.1494, found:
222.1496.
[410] [Preparation Example 37] Preparation of (S)-2-(1,3
dioxoisoindolin-2-yl)-4-methylpentanylhydroxamic acid
PLUS International IP Law Firm Our ref. PCT2018-151
-- 0 0 N,0 N'0H
O H
[411] Prepared from (S)-2-(1,3
dioxoisoindolin-2-yl)-4-methylpentanoic acid by Method D;
White solid (0.45 g, 81%); m.p. 155-157°C; 1H NMR (600 MHz,
CDCl 3 , one proton can't detected due to broadness) 5 9.33
(s, 1H), 7.87 (dd, J = 5.5, 3.1 Hz, 2H), 7.76 (dd, J = 5.5,
3.0 Hz, 2H), 5.01 (dd, J = 11.2, 5.2 Hz, 1H), 2.34-2.20 (m,
1H), 1.83 (ddd, J = 14.2, 9.4, 5.3 Hz, 1H), 1.46 (q, J =
7.8, 7.0 Hz, 1H), 0.93 (dd, J = 6.7, 2.3 Hz, 6H); 13C NMR
(150 MHz, CDCl3) 5 168.1, 167.8, 134.5, 131.4, 123.7, 51.4,
37.5, 25.0, 22.9, 21.3; IR (cm-1) 3228, 2957, 1715, 1644,
1380, 717; HRMS (EI) m/z calcd. for C1 4 H1 6 N2 0 4 [M]+: 276.1110,
found: 276.1111.
[412] [Preparation Example 38] Preparation of (S)-2-(1,3
dioxoisoindolin-2-yl)-4-phenylbutanylhydroxamic acid
-- 0 0 N, N'OH
O H
[413] Prepared from (S)-2-(1,3
dioxoisoindolin-2-yl)-4-phenylbutanoic acid (3.0 mmol
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scale) by Method D; White solid (0.49 g, 76%); m.p. 114
116 0 C; 1H NMR (600 MHz, DMSO-d 6 ) 5 10.80 (s, 1H), 8.87 (s,
1H), 7.88-7.83 (m, 4H), 7.18 (t, J = 7.5 Hz, 2H), 7.11 (d,
J = 7.5 Hz, 2H), 7.07 (t, J = 7.4 Hz, 1H), 4.62 (dd, J =
10.4, 4.8 Hz, 1H), 2.58-2.51 (m, 2H), 2.48-2.41 (m, 2H);
3 1 C NMR (150 MHz, DMSO-d) o 167.7, 165.2, 140.6, 134.4,
131.7, 128.3, 128.3, 125.8, 123.1, 51.4, 32.1, 29.3; IR
(cm-1) 3303, 3165, 2954, 1695, 1653, 1386, 712; HRMS (EI)
m/z calcd. for CisH1 6 N 2 0 4 [M]+: 324.1110, found: 324.1112.
[414] [Preparation Example 39] Preparation of (R)-3-(1,3
dioxoisoindolin-2-yl)-4-methylpentanyl hydroxamic acid
0 OH H N'
/ 0
[415] Prepared from (R)-3-(1,3
dioxoisoindolin-2-yl)-4-methylpentanoic acid(2.0 mmol
scale) by Method B; White solid (0.39 g, 71%); m.p. 154
156 0 C; 1H NMR (400 MHz, DMSO-d 6 ) 5 10.44 (s, 1H), 8.66 (s,
1H), 7.86-7.79 (m, 4H), 4.17 (td, J = 9.8, 4.8 Hz, 1H),
2.75 (dd, J = 14.7, 10.2 Hz, 1H), 2.56 (dd, J = 14.7, 4.7
Hz, 1H), 2.24-2.09 (m, 1H), 0.97 (d, J = 6.7 Hz,3H), 0.77
(d, J= 6.7 Hz, 3H); 13C NMR (100 MHz, DMSO-d6) 5 168.4,
167.2, 134.9, 131.6, 123.5, 54.5, 33.2, 31.0, 20.4, 20.0;
IR (cm-1) 3255, 2963, 2872, 1695, 1359, 719; HRMS (EI) m/z
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calcd. for Ci 4 H 1 6 N 2 0 4 [M]+: 276.1110, found: 276.1113.
[416] [Preparation Example 40] Preparation of 2-(1-((1,3
dioxoisoindolin-2-yl)methyl)cyclohexyl)acetylhydroxamic
acid
0 0 N NOH
O H
[417] Prepared from 2-(1-((1,3
dioxoisoindolin-2-yl)methyl)cyclohexyl)acetic acid (2.0
mmol scale) by Method D: White solid (0.43 g, 68%); m.p.
152-154°C; 'H NMR (400 MHz, DMSO-d 6 ) 5 10.40 (s, 1H), 8.77
(s, 1H), 7.85 (m, 4H), 3.65 (s, 2H), 2.06 (s, 2H), 1.61
3 1.06 (m, 10H); 1 C NMR(100 MHz, DMSO-d6 ) o 169.5, 167.8,
135.0, 132.4, 123.7, 46.8, 38.9, 38.8, 33.2, 25.9, 21.8; IR
(cm-1) 3274, 3140, 2922, 2868, 1697, 1396, 713; HRMS (EI)
m/z calcd. for Ci 7 H2oN20 4 [M]+: 316.1423, found: 316.1422.
[418] [Preparation Example 41] Preparation of tert-butyl
([1-{2-(hydroxyamino)-2
oxoethyllcyclohexyl]methyl)carbamate
H O O N , OH H
[419] Prepared from 2-(1-[{(tert
butoxycarbonyl)amino}methyl]cyclohexyl)acetic acid(2.0 mmol
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scale) by Method B; White solid (0.39 g, 68%); m.p. 129
131°C; 1H NMR (400 MHz, DMSO-d 6 ) 5 10.40 (s, 1H), 8.75 (s,
1H), 6.65 (s, 1H), 2.94 (d, J = 6.3 Hz, 2H), 1.88 (s, 2H),
3 1.40-1.14 (m, 19H); 1 C NMR (100 MHz, DMSO-d 6 ) 5 167.8,
156.5, 78.0, 47.3, 40.5, 37.2, 33.3, 28.7, 26.1, 21.5; IR
(cm-1) 3244, 2926, 1683, 1651, 1508, 1453, 1365, 1250,
1166; HRMS (FAB) m/z calcd. for C1 4 H 2 6N 2 0 4 [M+H]+: 287.1971,
found: 287.1968.
[420] [Preparation Example 42] Preparation of anti-(Z)-2
(3-oxo-2-(pent-2-en-1-yl)cyclopentyl)acetyl hydroxamic acid
NHOH
0
0
[421] Prepared from Jasmonic acid by Method
D; White solid (0.35 g, 78%); m.p. 91-93°C; 1H NMR (400 MHz,
DMSO-d6) 5 10.40 (s, 1H), 8.72 (s, 1H), 5.34 (q, J = 7.8 Hz,
1H), 5.23-5.14 (m, 1H), 2.27-2.11 (m, 5H), 2.04-1.86 (m,
6H), 1.43-1.30 (m, 1H) , 0.87 (t, J = 7. 5 Hz, 3H) ; 13 C NMR
(150 MHz, DMSO-d 6 ) 5 219.2, 168.1, 133.3, 126.1, 53.8, 38.0,
37.7, 37.4, 26.9, 25.3, 20.5, 14.5; IR (cm-1) 3206, 2931,
1733, 1647, 733, 701; HRMS (EI) m/z calcd. for Ci 2 HigNO3
[M]+: 225.1365, found: 225.1366.
[422] [Preparation Example 43] Preparation of (4R)-4
((3R,8R,9S,10S,13R,14S,17R)-3-methoxy-10,13
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dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17
yl)pentanoyl hydroxamic acid
NOH H
MeO'
[423] Prepared from 3ca-methyl
lithocholic acid (5.0 mmol scale) by Method B; White solid
(1.38 g, 68%); m.p.160-162°C; 'H NMR (600 MHz, DMSO-d6)5
10.31 (s, 1H), 8.63 (s, 1H), 3.21 (s, 3H), 3.10 (tt, J =
10.2, 4.3 Hz, 1H), 1.99-1.90 (m, 2H), 1.83 (dq, J = 31.7,
12.8, 10.5 Hz, 3H), 1.76-1.62 (m, 3H), 1.55 (dd, J = 23.8,
11.6 Hz, 3H), 1.33 (t, J = 10.3 Hz, 6H), 1.23-1.11 (m, 5H),
1.10-0.99 (m, 5H), 0.92-0.86 (m, 7H), 0.61 (s, 3H); 13 C NMR
(150 MHz, DMSO-d 6 , one carbon merged to solvent peak) 5
169.9, 79.9, 56.4, 56.0, 55.2, 42.7, 41.8, 40.1, 35.8, 35.3,
35.3, 34.9, 32.8, 31.9, 29.6, 28.2, 27.3, 26.9, 26.5, 24.3,
23.7, 20.6, 18.7, 12.3; IR (cm-1) 3224, 2925, 2861, 1650,
1446, 1372, 1091; HRMS (ESI) m/z calcd. for C 2 5 H 4 3 NO 3 [M+H]+:
406.3316, found: 406.3286.
[424] [Preparation Example 44] Preparation of 3,7
dimethyloct-6-enoylhydroxamic acid
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0 NHOH
[425] Prepared from citronellic acid
(5.0 mmol scale) by Method B; White solid (0.62 g, 67%);
m.p. 49-51°C; 1H NMR (600 MHz,CDCl 3 ) 5 9.13 (br, 1H), 8.63
(s, 1H), 5.05 (t, J = 7.3 Hz, 1H), 2.15 (dd, J = 13.6, 5.4
Hz, 1H), 2.03-1.91 (m, 3H), 1.88 (dd, J = 13.6, 8.6 Hz, 1H),
1.66 (s, 3H), 1.57 (s, 3H), 1.34 (td, J= 14.9, 14.3, 6.0
Hz, 1H), 1.19 (dt, J = 13.3, 6.7 Hz, 1H), 0.91 (d, J = 6.5
3 Hz, 3H); 1 C NMR (150 MHz, CDCl3) 5 171.2, 131.7, 124.1,
40.5, 36.7, 30.2, 25.7, 25.4, 19.3, 17.6; IR (cm-1) 3191,
2963, 2913, 1632, 1451, 735; HRMS (EI) m/z calcd. for
CioHigNO 2 [M]+: 185.1416, found: 185.1417.
[426] [Preparation Example 45] Preparation of (S)-2
((2R,4aS)-4a,8-dimethyl-7-oxo-1,2,3,4,4a,7
hexahydronaphthalen-2-yl)propanoyl hydroxamic acid
0 HOHN 0
[427] Prepared from (S)-2-((2R,4aS)-4a,8
dimethyl-7-oxo-1,2,3,4,4a,7-hexahydronaphthalen-2
yl)propanoic acid (1.0 mmol scale) by Method B; White solid
(0.15 g, 58%); m.p. 119-121°C; 'H NMR (400 MHz, acetone
d 6 ,two protons can't detected due to broadness) 5 6.83 (d,
J = 9.8 Hz, 1H), 6.07 (d, J = 9.8 Hz, 1H), 2.84-2.74 (m,
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1H), 2.26-2.14 (m, 1H), 1.94-1.85 (m, 1H), 1.83-1.71 (m,
4H), 1.60-1.41 (m, 2H), 1.32-1.19 (m, 1H), 1.19 (s, 3H),
3 1.14-1.09 (m, 4H); 1 C NMR (100 MHz, acetone-d) 5 185.2,
172.6, 159.4, 156.6, 128.7, 125.9, 43.0, 42.6, 40.3, 37.9,
31.8, 24.7, 22.9, 15.0, 9.8; IR (cm-1) 3186, 2921, 1650,
1596, 1451, 949, 834; HRMS (EI) m/z calcd. for C 1 5 H 2 1NO3
[M]+: 263.1521, found: 263.1519.
[428] Preparation Example IV: Preparation of 3-substituted
1,4,2-dioxazol-5-one compound
[429] A hydroxamic acid compound (5.0 mmol) was dissolved
in dichloromethane (50 mL), 1,1'-carbonyldiimidazole (0.81
g, 5.0 mmol) was added thereto all together at room
temperature, and the mixture was stirred for 30 minutes.
After the reaction was completed, the product was quenched
with 1 N HCl (30 mL), extracted with dichloromethane (50
mLx3), and dried with magnesium sulfate, and the solvent
was removed under reduced pressure. The residue was
filtered with silica and washed with dichloromethane (10
mlx2), and then the filtrate was distilled under reduced
pressure to obtain the title compound.
[430] The following compound was prepared in the same
manner as in the above, except that the starting material
was different.
[431] [Preparation Example 46] Preparation of 3-(3
phenylpropyl)-1,4,2-dioxazol-5-one
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0
[432] Colorless liquid (0.82g, 80%); 'H
NMR (600 MHz, CDCl 3 ) 6 7.32 (t, J = 7.5 Hz, 2H), 7.23 (t, J
= 7.3 Hz, 1H), 7.18 (d, J = 7.5 Hz, 2H), 2.75 (t, J = 7.4
Hz, 2H), 2.62 (t, J = 7.5 Hz, 2H), 2.07 (p, J = 7.4 Hz,
2H); 13 C NMR (150 MHz, CDCl 3 ) 5 166.4, 154.0, 139.7, 128.6,
128.4, 126.5, 34.5, 25.9, 24.0; IR (cm-1) 3207, 2913, 1827,
1634, 1452, 980; HRMS (EI) m/z calcd. for C1iHiiNO 3 [M]+:
205.0739, found: 205.0737.
[433] [Preparation Example 47] Preparation of 3-(3-(4
bromophenyl)propyl)-1,4,2-dioxazol-5-one
0 Br O N
[434] White solid (1.3 g, 93%); 1H NMR
(400 MHz, CDCl 3 ) 5 7.44 (d, J = 8.2 Hz, 2H), 7.06 (d, J =
8.2 Hz, 2H), 2.70 (t, J = 7.5 Hz, 2H), 2.62 (t, J = 7.4 Hz,
2H), 2.04 (p, J = 7.4 Hz, 2H); 1 3 C NMR (150 MHz, CDCl3) 5
166.2, 154.0, 138.7, 131.8, 130.1, 120.4, 33.9, 25.7, 23.9;
IR (cm-1) 2925, 1867, 1826, 1631, 1152, 985; HRMS (EI) m/z
calcd. for C11HioBrNO 3 [M]+: 282.9844, found: 282.9843.
[435] [Preparation Example 48] Preparation of 3-(3-(4
fluorophenyl)propyl)-1,4,2-dioxazol-5-one
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0 F
[436] - Colorless liquid (0.41 g, 90%);
1H NMR (600 MHz, CD 2 Cl 2 ) 5 7.22-7.12 (m, 2H), 7.07-6.95 (m,
2H), 2.72 (t, J = 7.5 Hz, 2H), 2.63 (t, J = 7.5 Hz, 2H),
2.03 (p, J = 7.5 Hz, 2H); 13 C NMR (150 MHz, CD 2 Cl 2 ) 5 166.6,
161.5 (d, J = 243.4 Hz), 154.1, 135.9 (d, J = 3.1 Hz),
129.9 (d, J = 7.8 Hz), 115.2 (d, J = 21.3 Hz), 33.7, 26.0,
24.0; 1 9 F NMR (564 MHz, CD 2Cl 2 ) 5-117.7(m); IR (cm-1) 2934,
1870, 1825, 1508, 1218, 1150, 981; HRMS (EI) m/z calcd. for
CiiHioFNO3 [M]+: 223.0645, found: 223.0646.
[437] [Preparation Example 49] Preparation of 3-(3-(4
nitrophenyl)propyl)-1,4,2-dioxazol-5-one
0 0 2N 04 N
[438] White solid (1.0 g, 81%); 'H
NMR (600 MHz, CDCl3) 5 8.18 (d, J = 8.6 Hz, 2H), 7.36 (d, J
= 8.6 Hz, 2H), 2.86 (t, J = 7.7 Hz, 2H), 2.67 (t, J = 7.4
Hz, 2H), 2.12 (p, J = 7.5 Hz, 2H); 13C NMR (150 MHz, CDCl 3 )
165.9, 153.8, 147.5, 146.9, 129.2, 124.0, 34.4, 25.4,
24.1; IR (cm-1) 1828, 1536, 1346, 1152, 990, 948; HRMS (EI)
m/z calcd. for CliHioN2 05 [M]+:250.0590, found: 250.0592.
[439] [Preparation Example 50] Preparation of 3-(3-(4
methoxyphenyl)propyl)-1,4,2-dioxazol-5-one
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0 MeO
[440] Yellowish oil (1.1 g, 95%); 1H
NMR (600 MHz, CDCl 3 ) 6 7.09 (d, J = 8.3 Hz, 2H), 6.85 (d, J
= 8.3 Hz, 2H), 3.80 (s, 3H), 2.69 (t, J = 7.4 Hz, 2H), 2.60
(t, J = 7.4 Hz, 2H), 2.03 (p, J = 7.4 Hz, 2H); 1 3 C NMR (150
MHz, CDCl 3 ) 5 166.5, 158.3, 154.1, 131.7, 129.4, 114.1,
55.3, 33.6, 26.1, 23.9; IR (cm-1) 2936, 1870, 1825, 1510,
1242, 981; HRMS (EI) m/z calcd. for C1 2 Hi 3NO 4 [M]+: 235.0845,
found: 235.0846.
[441] [Preparation Example 51] Preparation of tert-butyl
[4-{3-(5-oxo-1,4,2-dioxazol-3-yl)propyl}phenyl]carbamate
H O ON
[442] Prepared on a 1.2 mmol
scale. Due to the stability of a Boc group, the desired
compound was obtained through a silica filter directly
using dichloromethane without quenching with 1 N HCl after
the reaction. White solid (0.30 g, 78%); 1H NMR (600 MHz,
CDCl 3 ) 5 7.28 (d, J = 7.9 Hz, 2H), 7.07 (d, J = 8.5 Hz, 2H),
6.43 (s, 1H), 2.66 (t, J = 7.3 Hz, 2H), 2.58 (t, J = 7.5 Hz,
2H), 2.00 (p, J = 7.5 Hz, 2H), 1.49 (s, 9H); 1 3C NMR(150
MHz, CDCl3) o 166.4, 154.1, 152.8, 136.8, 134.4, 128.9,
118.9, 80.5, 33.8, 28.3, 25.9, 23.9; IR (cm-1) 3334, 2978,
1870, 1825, 1703, 1520, 1151; HRMS (FAB) m/z calcd. for
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C1 6H 2 oN 2 0 5 [M+H]+: 321.1450, found:321.1448.
[443] [Preparation Example 52] Preparation of 3-(2-Methyl
4-phenylbutan-2-yl)-1,4,2-dioxazol-5-one
0 04 N
[444] Colorless liquid (0.92 g, 79%); 1H
NMR (600 MHz, CDCl 3 ) 6 7.29 (t, J = 7.5 Hz, 2H), 7.21 (t, J
= 7.4 Hz, 1H), 7.16 (d, J = 7.6 Hz, 2H), 2.64-2.59 (m, 2H),
3 1.98-1.93 (m, 2H), 1.40 (s, 6H) ; 1 C NMR (150 MHz, CDCl3) 5
171.3, 154.3, 140.4, 128.5, 128.3, 126.3, 41.2, 35.9, 30.8,
24.2; IR (cm-1) 2978, 1869, 1824, 1110, 974; HRMS (EI) m/z
calcd. for Ci 3 Hi 5NO3 [M]+: 233.1052, found: 233.1051.
[445] [Preparation Example 53] Preparation of 3-(4
phenylbutan-2-yl)-1,4,2-dioxazol-5-one
0 04 N
[446] Colorless liquid (0.42 g, 95%); 1H
NMR (600 MHz, CD 2 Cl 2 ) 5 7.30 (t, J = 7.4 Hz, 2H), 7.24-7.16
(m, 3H), 2.91-2.81 (m, 1H), 2.76-2.64 (m, 2H), 2.14-2.03 (m,
1H), 1.97-1.86 (m, 1H), 1.35 (d, J = 7.0 Hz, 3H); 13 C NMR
(150 MHz, CD2Cl2) 5 169.6, 154.2, 140.4, 128.5, 128.3,
126.2, 34.0, 32.6, 30.6, 16.0; IR (cm-1) 3332, 1870, 1826,
1264, 976, 734; HRMS (EI) m/z calcd. for C12Hi3NO3 [M]+:
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219.0895, found: 219.0893.
[447] [Preparation Example 54] Preparation of 3-(2-methyl
3-phenylpropyl)-1,4,2-dioxazol-5-one
0 04 O
[448] Prepared on a 3.0 mmol scale.
Yellowish oil (0.61 g, 95%); 1H NMR (600 MHz, CDCl 3 ) 5 7.31
(t, J = 7.3 Hz, 2H), 7.24 (t, J = 7.3 Hz, 1H), 7.16 (d, J =
7.2 Hz, 2H), 2.70-2.59 (m, 3H), 2.44 (dd, J = 15.4, 8.0 Hz,
1H), 2.30 (dq, J = 14.0, 6.9 Hz, 1H), 1.05 (d, J = 6.6 Hz,
3 3H); 1 C NMR (150 MHz, CDCl 3 ) 5 165.9, 154.0, 138.8, 129.1,
128.6, 126.6, 42.7, 32.1, 31.0, 19.6; IR (cm-1) 2929, 1875,
1826, 1631, 1145, 980; HRMS (EI) m/z calcd. for C1 2 Hi 3 NO3
[M]+: 219.0895, found: 219.0894.
[449] [Preparation Example 55] Preparation of 3-((2,3
dihydro-1H-inden-2-yl)methyl)-1,4,2-dioxazol-5-one
0 N
[450] Colorless oil (0.43 g, 40%); 1H NMR
(600 MHz, CDCl 3 ) 6 7.24-7.19 (m, 2H), 7.19-7.14 (m, 2H),
3.21 (dd, J = 15.6, 7.8 Hz, 2H), 2.91 (hept, J= 7.8, 7.2
Hz, 1H), 2.78 (d, J = 7.4 Hz, 2H), 2.75 (dd, J= 15.6, 6.4
3 Hz, 2H); 1 C NMR (150 MHz, CDCl3) 5 165.9, 154.0, 141.3,
126.8, 124.6, 38.7, 35.5, 30.3; IR (cm-1) 1878, 1820, 1353,
1143, 990, 744; HRMS (EI) m/z calcd. for Cl2HiiNO3 [M]+:
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217.0739, found: 217.0740.
[451] [Preparation Example 56] Preparation of 3-(2
ethylphenyl)-1,4,2-dioxazol-5-one
0 04 ) N
[452] Prepared at 3.0 mmol scale. Colorless
oil (0.28 g, 48%); 1H NMR (600 MHz, CDCl3) 5 7.75 (d, J =
7.8 Hz, 1H), 7.56 (t, J = 7.7 Hz, 1H), 7.41 (d, J = 7.8 Hz,
1H), 7.37 (t, J = 7.7 Hz, 1H), 2.97 (q, J = 7.5 Hz, 2H),
1.27 (t, J = 7.5 Hz, 3H); 13 C NMR (150 MHz, CDCl,) 6 163.9,
153.7, 145.3, 133.4, 130.4, 129.1, 126.5, 118.6, 27.6,
14.9; IR (cm-1) 1857, 1827, 1608, 1339, 1055, 969, 753;
HRMS (EI) m/z calcd. for CioH 9NO 3 [M]+: 191.0582, found:
191.0581.
[453] [Preparation Example 57] Preparation of 3-(2
benzylphenyl)-1,4,2-dioxazol-5-one
0 04 N
[454] White solid (0.77 g, 61%); 'H NMR (600
MHz, CDCl3) 6 7.79 (d, J = 7.9 Hz, 1H), 7.55 (t, J = 7.6 Hz,
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1H), 7.41 (t, J= 7.6 Hz, 1H), 7.32-7.28 (m, 3H), 7.23 (t,
J = 7.4 Hz, 1H), 7.13 (d, J = 7.6 Hz, 2H), 4.34 (s, 2H);
3 1 C NMR (150 MHz, CDCl3) 5 163.7, 153.5, 141.7, 138.8, 133.3,
131.9, 129.3, 129.0, 128.6, 127.0, 126.5, 119.3, 39.9; IR
(cm-1) 1861, 1829, 1348, 1173, 1042, 978; HRMS (EI) m/z
calcd. for C1 5 H 1 1NO 3 [M]+: 253.0739, found: 253.0739.
[455] [Preparation Example 58] Preparation of 3-(3
(benzofuran-2-yl)propyl)-1,4,2-dioxazol-5-one
00 0 N
[456] Colorless oil (1.21 g, 99%) ; 1H NMR (400 MHz, CDCl3 ) 5 7.54-7.49 (m, 1H), 7.43 (d, J = 8.2
Hz, 1H), 7.28-7.18 (m, 2H), 6.47 (s, 1H), 2.93 (t, J = 7.1
Hz, 2H), 2.72 (t, J = 7.5 Hz, 2H), 2.20 (p, J = 7.3 Hz,
3 2H); 1 C NMR (150 MHz, CDCl 3 ) 5 166.1, 156.3, 154.8, 154.0,
128.5, 123.7, 122.7, 120.5, 110.9, 103.4, 27.2, 24.0, 22.6;
IR (cm-1) 1880, 1860, 1830, 1151, 981, 751; HRMS (EI) m/z
calcd. for C13HiiN0 4 [M]+: 245.0688, found: 245.0690.
[457] [Preparation Example 59] Preparation of 3-(3
(thiophen-2-yl)propyl)-1,4,2-dioxazol-5-one
O N
[458] Colorless liquid (0.99g, 94%); 1H
NMR (600 MHz, CDCl 3 ) 6 7.17 (dd, J = 5.1, 1.2 Hz, 1H), 6.94
(dd, J = 5.2, 3.4 Hz, 1H), 6.85-6.81 (m, 1H), 2.98 (t, J=
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7.2 Hz, 2H), 2.67 (t, J = 7.5 Hz, 2H), 2.11 (p, J = 7.3 Hz,
3 2H); 1 C NMR (150 MHz, CDCl 3 ) 5 166.2, 154.0, 142.2, 127.0,
125.2, 123.9, 28.6, 26.2, 23.8; IR (cm-1) 1868, 1823, 1635,
1148, 980, 695; HRMS (EI) m/z calcd. for C 9H 9NO3S [M]+:
211.0303, found: 211.0301.
[459] [Preparation Example 60] Preparation of 3-isopentyl
1,4,2-dioxazol-5-one
0
~~0 N
[460] Colorless oil (0.67 g, 85%); 1H NMR (600
MHz, CDCl,) 5 2.61 (t, J= 7.6 Hz, 2H), 1.68-1.57 (m, 3H),
0.94 (d, J = 6.4 Hz, 6H); 13C NMR (150 MHz, CDCl 3 ) 5 166.9,
154.2, 33.1, 27.4, 22.8, 21.9; IR (cm-1) 2960, 1865, 1825,
1147, 981, 761; HRMS (EI) m/z calcd. for C7 HiiNO3 [M]+:
157.0739, found: 157.0738.
[461] [Preparation Example 61] Preparation of 3-(2
cyclohexylethyl)-1,4,2-dioxazol-5-one
0
N
[462] - Colorless oil (0.95 g, 96%) ; 'H NMR
(600 MHz, CDCl3) 5 2.63 (t, J = 8.0 Hz, 2H), 1.73 (d, J =
10.9 Hz, 4H), 1.67 (d, J = 12.6 Hz, 1H), 1.61 (q, J = 7.3
Hz, 2H), 1.35-1.12 (m, 4H), 0.93 (q, J= 12.0 Hz, 2H); 13C
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NMR (150 MHz, CDCl 3 ) 5 167.0, 154.2, 36.8, 32.7, 31.7, 26.3,
26.0, 22.3; IR (cm-1) 2922, 2851, 1867, 1825, 1145, 974,
762; HRMS (EI) m/z calcd. for CioHi 5NO3 [M]+: 197.1052,
found: 197.1050.
[463] [Preparation Example 62] Preparation of 3-(2
isopropylphenyl)-1,4,2-dioxazol-5-one
0 04 SN
[464] Prepared on a 0.84 mmol scale; Colorless
oil (0.12 g, 67%); 'H NMR (600 MHz, CDCl 3 ) 5 7.69 (d, J =
8.0 Hz, 1H), 7.59 (t, J = 7.6 Hz, 1H), 7.53 (d, J = 8.0 Hz,
1H), 7.35 (t, J = 7.6 Hz, 1H), 3.60 (hept, J = 6.8 Hz, 1H),
1.29 (d, J = 6.8 Hz, 6H); 1 3C NMR (150 MHz, CDCl 3 ) 5 164.1,
153.8, 150.0, 133.5, 129.3, 126.9, 126.4, 118.3, 30.3,
23.6; IR (cm-1) 2967, 1858, 1829, 1337, 1047, 970, 758;
HRMS (EI) m/z calcd. for C11HiiNO3 [M]+: 205.0739, found:
205.0737.
[465] [Preparation Example 63] Preparation of (S)-3-(3
Methylpentyl)-1,4,2-dioxazol-5-one
0 ~0 N
[466]
[467] Prepared on a 7.65 mmol scale; colorless liquid (0.93
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g, 71%, 2 steps yield from carboxylic acid) ; 1H NMR (400
MHz, CDCla) o 2.73-2.56 (m, 2H), 1.82-1.71 (m, 1H), 1.60
1.49 (m, 1H), 1.49-1.35 (m, 2H), 1.29-1.18 (m, 1H), 0.97
3 0.88 (m, 6H); 1 C NMR (100 MHz, CDCl,) 5 167.2, 154.4, 33.9,
31.2, 29.1, 22.8, 18.7, 11.3; IR (cm-1) 2962, 1859, 1825,
1147, 979; HRMS (ESI) m/z calcd. for CsH13NO 3 [M+Na]+:
194.0788, found: 190.0794.
[468] [Preparation Example 64] Preparation of 3-butyl
1,4,2-dioxazol-5-one
0
N
[469] Prepared on a 3.5 mmol scale;
Colorless liquid (0.39g, 78%); 1H NMR (600 MHz, CDCl3) 5
2.63 (t, J = 7.5 Hz, 2H), 1.71 (p, J = 7.6 Hz, 2H), 1.44 (h,
J = 7.4 Hz, 2H), 0.97 (t, J = 7.4 Hz, 3H); 13 C NMR (150 MHz,
CDCl 3 ) 5 166.7, 154.2, 26.5, 24.4, 21.8, 13.4; IR (cm-1)
2963, 1824, 1634, 1148, 980, 761; HRMS (EI) m/z calcd. for
C6H9NO3 [M]+: 143.0582, found:143.0583.
[470] [Preparation Example 65] Preparation of 3
(cyclopentylmethyl)-1,4,2-dioxazol-5-one
0
[471] Prepared on a 4.4 mmol scale;
Colorless liquid (0.70g, 94%); 1H NMR (600 MHz, CDCl 3 ) 5
2.60 (d, J = 7.4 Hz, 2H), 2.23 (hept, J = 7.8 Hz, 1H), 1.88
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(dq, J = 11.9, 6.8 Hz, 2H), 1.71-1.64 (m, 2H), 1.64-1.56 (m,
2H), 1.24 (dq, J = 15.0, 7.6 Hz, 2H); 13 C NMR (150 MHz,
CDCl3) 5 166.4, 154.2, 35.9, 32.3, 30.5, 24.9; IR (cm-1)
2952, 2869, 1868, 1825, 1631, 1149, 980; HRMS (EI) m/z
calcd. for CsHi1 NO 3 [M]+: 169.0739, found: 169.0739.
[472] [Preparation Example 66] Preparation of 3
((adamantan-1-yl)methyl)-1,4,2-dioxazol-5-one
,0 N
[473] White solid (1.13 g, 96%); 1H NMR (600 MHz,
CDCl 3 ) 5 2.36 (s, 2H), 2.01 (s, 3H), 1.72 (d, J = 12.2 Hz,
3H), 1.65-1.58 (m, 9H); 13C NMR (150 MHz, CDCl3 ) 5 165.0,
154.3, 42.1, 38.8, 36.3, 33.2, 28.3; IR (cm-1) 2903, 2885,
2848, 1813, 1152, 985; HRMS (EI) m/z calcd. for Ci 3H1 7NO 3
[M]+: 235.1208, found:235.1206.
[474] [Preparation Example 67] Preparation of 3-neopentyl
1,4,2-dioxazol-5-one
[475] Colorless oil (0.55 g, 70%); 1H NMR (600
MHz, CDCl3) 5 2.51 (s, 2H), 1.08 (s, 9H); 1 3 C NMR (150 MHz,
CDCl 3 ) 5 165.6, 154.2, 38.4, 31.3, 29.4; IR (cm-1) 2963,
1829, 1629, 1352, 1143, 981.
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[476] [Preparation Example 68] Preparation of 3-(pent-4-en
1-yl)-1,4,2-dioxazol-5-one
0 04 N
[477] Colorless oil (0.44 g, 60%); 1H NMR
(600 MHz, CDCla) o 5.76 (ddt, J = 17.0, 10.4, 6.7 Hz, 1H),
5.12-5.04 (m, 2H), 2.64 (t, J = 7.5 Hz, 2H), 2.18 (q, J=
6.6 Hz, 2H), 1.84 (p, J = 7.4 Hz, 2H); 13 C NMR (150 MHz,
CDCl,) 6 166.5, 154.1, 136.2, 116.6, 32.4, 23.9, 23.5; IR
(cm-1) 1868, 1824, 1638, 1148, 979, 761; HRMS (EI) m/z
calcd. for C 7H 9 NO 3 [M]+: 155.0582, found: 155.0584.
[478] [Preparation Example 69] Preparation of (E)-3-(5
phenylpent-4-en-1-yl)-1,4,2-dioxazol-5-one
0 04
[479] Prepared on a 2.6 mmol scale;
Colorless oil (0.36 g, 96%); 'H NMR (600 MHz, CDCl3) 6 7.35
(d, J = 7.4 Hz, 2H), 7.31 (t, J = 7.2 Hz, 2H), 7.23 (t, J =
7.1 Hz, 1H), 6.45 (d, J = 15.8 Hz, 1H), 6.15 (dt, J = 15.7,
6.9 Hz, 1H), 2.68 (t, J = 7.4 Hz, 2H), 2.35 (q, J = 7.0 Hz,
2H), 1.93 (q, J = 7.3 Hz, 2H); 13 C NMR (150 MHz, CDCl3) 6
166.5, 154.1, 137.0, 132.0, 128.6, 127.7, 127.4, 126.0,
31.8, 24.1, 24.1; IR (cm-1) 1868, 1824, 1633, 1146, 965,
740; HRMS (EI) m/z calcd. for C13H1 3 N0 3 [M]+: 231.0895,
found: 231.0896.
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[480] [Preparation Example 70] Preparation of 3-(4
phenylpent-4-en-1-yl)-1,4,2-dioxazol-5-one
0
0 N
[481] Prepared on a 2.6 mmol scale;
Colorless oil (0.58 g, 94%); 1H NMR (600 MHz, CDCl 3 ) 5
7.40-7.33 (m, 4H), 7.30 (t, J = 7.0 Hz, 1H), 5.35 (s, 1H),
5.11 (s, 1H), 2.67-2.60 (m, 4H), 1.88 (p, J = 8.1, 7.3 Hz,
3 2H); 1 C NMR (150 MHz, CDCl3) 5 166.4, 154.0, 146.3, 140.1,
128.5, 127.8, 126.1, 114.0, 34.1, 24.0, 22.7; IR (cm-1)
1870, 1825, 1630, 1147, 979, 704; HRMS (EI) m/z calcd. for
Ci 3 H1 3 NO 3 [M]+: 231.0895, found: 231.0896.
[482] [Preparation Example 71] Preparation of 3-(5
phenylpent-4-yn-1-yl)-1,4,2-dioxazol-5-one
0 o-k 1~0 N
[483] Colorless oil (1.0 g, 88%); 1H
NMR (400 MHz, CD 2 Cl 2 ) 5 7.42-7.36 (m, 2H), 7.32-7.27 (m,
3H), 2.84 (t, J = 7.5 Hz, 2H), 2.58 (t, J = 6.7 Hz, 2H),
2.02 (p, J = 7.0 Hz, 2H); 13 C NMR (150 MHz, CD 2 Cl 2 ) 5 166.5,
154.2, 131.4, 128.3, 127.9, 123.3, 87.4, 82.0, 23.8, 23.5,
18.5; IR (cm-1) 1870, 1823, 1634, 1146, 979, 754, 691; HRMS
(EI) m/z calcd. for C1 3 HiiNO 3 [M]+: 229.0739, found: 229.0741.
[484] [Preparation Example 72] Preparation of 3-(6
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phenylhex-4-yn-1-yl)-1,4,2-dioxazol-5-one
0
[485] Prepared on a 1 mmol scale;
Yellow oil (0.18 g, 75%); 1H NMR (600 MHz, CD 2 Cl 2 ) 5 7.36
7.28 (m, 4H), 7.23 (t, J= 6.5 Hz, 1H), 3.58 (s, 2H), 2.79
(t, J = 7.5 Hz, 2H), 2.44-2.36 (m, 2H), 1.94 (p, J = 7.0 Hz,
3 2H); 1 C NMR (150 MHz, CD 2 Cl 2 ) 5 166.5, 154.2, 137.2, 128.4,
127.7, 126.4, 79.8, 79.6, 24.9, 23.8, 23.7, 17.9; IR (cm-1)
2939, 1869, 1825, 1636, 1149, 982, 760; HRMS (EI) m/z calcd.
for C1 4 H1 3 NO 3 [M]+: 243.0895, found: 243.0899.
[486] [Preparation Example 73] Preparation of 3-(hex-4-yn
1-yl)-1,4,2-dioxazol-5-one
N
[487] Prepared on a 1 mmol scale;
Colorless oil (0.16 g, 96%); 'H NMR (600 MHz, CD2Cl2) 5 2.77
(t, J = 7.5 Hz, 2H), 2.32-2.24 (m, 2H), 1.88 (p, J = 6.8 Hz,
3 2H), 1.77 (s, 3H); 1 C NMR (150 MHz, CD 2 Cl 2 ) 5 166.6, 154.2,
77.3, 76.5, 23.8, 23.7, 17.8, 3.0; IR (cm-1) 2920, 1869,
1825, 1634, 1148, 982, 759; HRMS (EI) m/z calcd. for CsH 9 NO3
[M]+: 167.0582, found: 167.0583.
[488] [Preparation Example 74] Preparation of 3-(2
benzylbutyl)-1,4,2-dioxazol-5-one
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0 04 N
'
[489] Prepared on a 1.2 mmol scale;
Colorless oil (0.27 g, 96%); 1H NMR (600 MHz, CDCl3 ) 5 7.31
(t, J = 7.5 Hz, 2H), 7.23 (t, J = 7.2 Hz, 1H), 7.16 (d, J =
7.5 Hz, 2H), 2.82 (dd, J = 13.9, 6.0 Hz, 1H), 2.56-2.50 (m,
3H), 2.12 (hept, J= 6.6 Hz, 1H), 1.45 (dh, J = 14.5, 7.2
Hz, 2H), 1.00 (t, J= 7.4 Hz, 3H); 13C NMR (150 MHz, CDCl3)
166.0, 154.0, 138.9, 129.1, 128.6, 126.6, 39.6, 38.4,
28.2, 26.2, 10.8; IR (cm-1) 2964, 1869, 1826, 1145, 979,
699; HRMS (FAB) m/z calcd. for Ci 3 Hi5 NO 3 [M+H]+: 234.1130,
found: 234.1133.
[490] [Preparation Example 75] Preparation of 3-(2-benzyl
3-methylbutyl)-1,4,2-dioxazol-5-one
0
[491] Prepared on a 1.2 mmol scale;
Colorless oil (0.24 g, 80%); 'H NMR (400 MHz, CD2Cl2) 5 7.29
(t, J = 7.3 Hz, 2H), 7.24-7.13 (m, 3H), 2.84 (dd, J = 13.9,
5.5 Hz, 1H), 2.58 (dd, J = 15.7, 6.5 Hz, 1H), 2.52-2.40 (m,
2H), 2.15-2.06 (m, 1H), 1.86-1.74 (m, 1H), 0.98 (dd, J =
3 19.0, 6.9 Hz, 6H); 1 C NMR (150 MHz, CD 2 Cl 2 ) 5 166.6, 154.1,
139.6, 129.0, 128.4, 126.3, 42.8, 36.6, 29.7, 26.0, 18.4;
IR (cm-1) 2960, 1869, 1825, 1631, 980, 699; HRMS (FAB) m/z
calcd. for Ci 4 Hi 7NO3 [M+H]+: 248.1287, found:248.1285.
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[492] [Preparation Example 76] Preparation of (S)-2-(3
methyl-i-(5-oxo-1,4,2-dioxazol-3-yl)butyl)isoindoline-1,3
dione
\ 04 / N 0
[493] White solid (0. 93 g, 62%) ; 1H NMR (400 MHz, CDCl,) 5 7.91 (dd, J = 5.5, 3.1 Hz, 2H), 7.80 (dd,
J = 5.5, 3.1 Hz, 2H), 5.43 (dd, J = 10.7, 4.7 Hz, 1H),
2.48-2.37 (m, 1H), 1.98 (ddd, J = 14.3, 9.6, 4.7 Hz, 1H),
1.67-1.56 (m, 1H), 0.99 (dd, J = 8.8, 6.6 Hz, 6H); 13C NMR
(150 MHz, CDCl 3 ) 6 166.8, 164.3, 153.3, 134.8, 131.2, 124.0,
43.7, 36.4, 24.5, 22.8, 21.2; IR (cm-1) 2959, 2924, 2876,
1830, 1716, 1380, 989, 756, 711; HRMS (EI) m/z calcd. for
Ci 5 H1 4 N 20 5 [M]+: 302.0903, found: 302.0904.
[494] [Preparation Example 77] Preparation of (S)-2-(1-(5
oxo-1,4,2-dioxazol-3-yl)-3-phenylpropyl)isoindoline-1,3
dione
- O 04 N, ,0 N 0
[495] Prepared on a 2.0 mmol scale; White
solid (0.44 g, 62%); 'H NMR (400 MHz, CDCl3)5 7.86 (dd, J=
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5.5, 3.0 Hz, 2H), 7.78 (dd, J = 5.5, 3.1 Hz, 2H), 7.20 (t,
J = 7.5 Hz, 2H), 7.14 (d, J = 6.6 Hz, 2H), 7.08 (t, J = 7.2
Hz, 1H), 5.36 (t, J = 4.8 Hz, 1H), 2.85-2.73 (m, 3H), 2.61
2.52 (m, 1H); 13 C NMR (150 MHz, CDCl3 ) 5 166.7, 163.9, 153.3,
138.9, 134.7, 131.2, 128.6, 128.3, 126.4, 123.9, 44.9, 31.8,
28.9; IR (cm-1) 1834, 1781, 1716, 1381, 754; HRMS (EI) m/z
calcd. for Ci 9 H1 4N 2 05 [M]+: 350.0903, found: 350.0900.
[496] [Preparation Example 78] Preparation of (R)-2-(3
Methyl-1-(5-oxo-1,4,2-dioxazol-3-yl)butan-2-yl)isoindoline
1,3-dione
0 0
,0 0 N
N'
/ 0
[497] Prepared on a 2.0 mmol scale; White
solid(0.22 g, 38%); 1H NMR (400 MHz, CDCl 3 ) 6 7.85-7.79 (m,
2H), 7.76-7.70 (m, 2H), 4.23 (ddd, J= 10.9, 9.9, 3.5 Hz,
1H), 3.60 (dd, J = 16.0, 11.0 Hz, 1H), 3.08 (dd, J = 16.0,
3.6 Hz, 1H), 2.57-2.41 (m, 1H), 1.10 (d, J = 6.7 Hz, 3H),
0.88 (d, J= 6.7 Hz, 3H); 13C NMR (100 MHz, CDCl 3 ) 6 168.2,
164.7, 153.7, 134.5, 131.3, 123.7, 53.8, 30.4, 25.8, 20.2,
19.7; IR (cm-1) 2967, 1865, 1828, 1703, 979, 719; HRMS (EI)
m/z calcd. for Ci 5 H1 4N20 5 [M]+: 302.0903, found: 302.0904.
[498] [Preparation Example 79] Preparation of 2-((1-((5
oxo-1,4,2-dioxazol-3
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yl)methyl)cyclohexyl)methyl)isoindoline-1,3-dione
- O
N ,, N 0
[499] Prepared on a 2.0 mmol scale;
White solid (0.36 g, 52%); 1H NMR (400 MHz, CDCl 3 ) 5 7.84
(dd, J = 5.5, 3.1 Hz, 2H), 7.74 (dd, J = 5.5, 3.1 Hz, 2H),
3.76 (s, 2H), 2.72 (s, 2H), 1.74-1.63 (m, 2H), 1.52-1.42 (m,
3 8H); 1 C NMR (100 MHz, CDCl3) 5 169.2, 165.2, 154.1, 134.4,
131.8, 123.6, 45.4, 38.7, 33.5, 32.0, 25.4, 21.4; IR (cm-1)
2922, 1824, 1707, 1390, 984, 711; HRMS (EI) m/z calcd. for
CisHisN 205 [M]+: 342.1216, found: 342.1212.
[500] [Preparation Example 80] Preparation of tert-butyl
([1-{(5-oxo-1,4,2-dioxazol-3
yl)methyllcyclohexyl]methyl)carbamate
O H O4 N , O O)
[501] Prepared at 1.0 mmol scale;
Colorless oil (0.23 g, 75%); 1H NMR (400 MHz, Methylene
Chloride-d2) 5 4.78 (s, 1H), 3.14 (d, J = 6.9 Hz, 2H), 2.62
3 (s, 2H), 1.62-1.33 (m, 19H); 1 C NMR (100 MHz, Methylene
Chloride-d2) 5 165.5, 156.1, 154.1, 79.1, 46.5, 38.1, 33.3,
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31.3, 28.0, 25.6, 21.3; IR (cm-1) 3349, 2929, 1829, 1698,
1628, 1510, 1455, 1365, 1246, 1163, 983, 763; HRMS (FAB)
m/z calcd. for Ci 5 H2 4 N20 5 [M+H]+: 313.1763, found: 313.1760.
[502] [Preparation Example 81] Preparation of anti-(Z)-3
((3-oxo-2-(pent-2-en-1-yl)cyclopentyl)methyl)-1,4,2
dioxazol-5-one
O.O
N 0
[503] Prepared on a 1.8 mmol scale;
Colorless oil (0.34 g, 77%); 'H NMR (600 MHz, CDCl 3 ) 5
5.53-5.47 (m, 1H), 5.23 (q, J= 8.7, 8.2 Hz, 1H), 3.04 (dd,
J = 15.6, 4.3 Hz, 1H), 2.63 (dd, J = 15.6, 9.2 Hz, 1H),
2.49-2.24 (m, 6H), 2.20-2.13 (m, 1H), 2.05 (p, J = 7.4 Hz,
2H), 1.98-1.93 (m, 1H), 1.62-1.54 (m, 1H), 0.97 (t, J = 7.6
3 Hz, 3H); 1 C NMR (150 MHz, CDCl3) 5 216.8, 165.1, 153.7,
134.8, 124.3, 53.8, 37.8, 37.4, 29.6, 27.0, 25.7, 20.6,
14.0; IR (cm-1) 2963, 1870, 1826, 1736, 1147, 979; HRMS
(EI) m/z calcd. for C13H1 7 NO 4 [M]+: 251.1158, found: 251.1155.
[504] [Preparation Example 82] Preparation of 3-((3R)-3
((3R,8R,9S,10S,13R,14S,17R)-3-methoxy-10,13
dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17
yl)butyl)-1,4,2-dioxazol-5-one
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4-.N'0
H
MeO"
[505] Prepared on a 3.0 mmol
scale; White solid (1.23 g, 95%); 'H NMR (600 MHz, CDCl3) 5
3.35 (s, 3H), 3.16 (dt, J = 10.9, 5.6 Hz, 1H), 2.66 (ddd, J
= 15.2, 7.4, 3.4 Hz, 1H), 2.57-2.48 (m, 1H), 1.94 (d, J =
12.4 Hz, 1H), 1.89-1.81 (m, 3H), 1.81-1.73 (m, 2H), 1.68 (q,
J = 12.7, 12.2 Hz, 1H), 1.59 (d, J = 11.8 Hz, 2H), 1.50
1.34 (m, 7H), 1.28-1.21 (m, 4H), 1.09 (dt, J = 33.9, 8.7 Hz,
H), 0.97 (d, J = 6.4 Hz, 3H), 0.94-0.92 (m, 4H), 0.65 (s,
3 3H); 1 C NMR (150 MHz, CDCl 3 ) 5 167.1, 154.2, 80.4, 56.4,
55.6, 55.5, 42.8, 42.0, 40.3, 40.1, 35.8, 35.3, 35.2, 34.9,
32.7, 30.6, 28.2, 27.3, 26.8, 26.3, 24.1, 23.4, 21.8, 20.8,
18.0, 12.0; IR (cm-1) 2923, 2865, 1856, 1822, 1634, 1091,
982; HRMS (EI) m/z calcd. for C26H 41 NO 4 [M]+: 431.3036,
found: 431.3033.
[506] [Preparation Example 83] Preparation of 3-(2,6
dimethylhept-5-en-1-yl)-1,4,2-dioxazol-5-one
0
[507] Prepared on a 3.2 mmol scale;
Colorless oil (577mg, 85%); 'H NMR (600 MHz, CDCl3) 5 5.06
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(t, J = 7.0 Hz, 1H), 2.61 (dd, J = 15.2, 5.8 Hz, 1H), 2.45
(dd, J= 15.2, 8.1 Hz, 1H), 2.00 (tdd, J = 27.5, 14.1, 7.0
Hz, 3H), 1.69 (s, 3H), 1.61 (s, 3H), 1.42 (td, J = 14.7,
6.3 Hz, 1H), 1.32 (dt, J = 13.7, 7.2 Hz, 1H), 1.02 (d, J =
3 6.7 Hz, 3H); 1 C NMR (150 MHz, CDCl 3 ) 5 166.1, 154.2, 132.4,
123.3, 36.3, 31.7, 29.8, 25.7, 25.1, 19.3, 17.7; IR (cm-1)
2961, 1875, 1828, 1632, 1145, 979, 761; HRMS (EI) m/z calcd.
for Cn1Hi7 N0 3 [M]+: 211.1208, found: 211.1209.
[508] [Preparation Example 84] Preparation of 3-((S)-1
((2R,4aS)-4a,8-dimethyl-7-oxo-1,2,3,4,4a,7
hexahydronaphthalen-2-yl)ethyl)-1,4,2-dioxazol-5-one
N
[509] Prepared on a 1 mmol scale; White
solid (0.14 g, 48%); 'H NMR (400 MHz, acetone-d6) 5 6.85 (d,
J = 9.9 Hz, 1H), 6.09 (d, J = 9.9 Hz, 1H), 3.14-3.04 (m,
1H), 2.95-2.85 (m, 1H), 2.24 (t, J = 12.7 Hz, 1H), 1.98
1.89 (m, 1H), 1.87-1.69 (m, 6H), 1.42-1.27 (m, 4H), 1.24 (s,
3 3H); 1 C NMR (100 MHz, acetone-d6) 5 185.8, 169.7, 158.9,
157.1, 155.3, 130.0, 126.6, 42.1, 40.8, 38.1, 36.8, 31.8,
24.3, 23.7, 13.3, 10.5; IR (cm-1) 2979, 2949, 2919, 1822,
1658, 1625, 980, 839; HRMS (EI) m/z calcd. for C 1 6 H 1 9 NO4
[M]+: 289.1314, found: 289.1312.
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[510] Example II: Preparation of gamma-lactam compound from
dioxazol-one compound
[511] [Example 14] Preparation of 5-phenylpyrrolidin-2-one
(1)
Metal complex J (2 mol %) O NaBArF 4 (2 mol %) I NH Ph N DCM, 40 °C, 12 h -CO 2 Ph
[512] (1)
[513] Metal complex J (2.4 mg, 2.0 mol%), sodium
tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (NaBArF4
, 4.5 mg, 2.0 mol%), and dichloromethane (2.4 mL) were added
to a well-dried vial under an argon atmosphere, the mixture
was stirred for 1 minute, 3-(3-phenylpropyl)-1,4,2
dioxazol-5-one (10.3 mg, 0.2 mmol) was added thereto, and
the vial was sealed under an argon atmosphere. Thereafter,
the reaction mixture was vigorously stirred at 40°C for 12
hours, cooled to room temperature, filtered with celite,
washed with dichloromethane (5 mLx4), and concentrated
under reduced pressure. The concentrated residue was
separated and purified with column chromatography (eluent:
n-hexane/10 % methanol-EtOAc solution, 2:1 - 1:1) to obtain
the desired compound (35 mg, 95%).
[514] 5-Phenylpyrrolidin-2-one (1)
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0
NH
[515] Catalyst J (2.4 mg, 2 mol%) was used.
White solid (31mg, 95%); 1H NMR (600 MHz,CDCl 3 ) 5 7.38-7.33
(m, 2H), 7.32-7.27 (m, 3H), 6.57 (br, 1H), 4.75 (t, J = 7.1
Hz, 1H), 2.60-2.52 (m, 1H), 2.49-2.35 (m, 2H), 2.00-1.92 (m,
3 1H); 1 C NMR (150 MHz, CDCl 3 ) 5 178.6, 142.5, 128.9, 127.8,
125.6, 58.1, 31.3, 30.3.
[516] Gamma-lactam compounds having various structures were
prepared in the same manner as in Example 14, except that
the starting material, the reaction temperature, the
catalyst, or the base was different, and the synthesis data
of the prepared gamma-lactam compounds are shown in the
following.
[517] [Example 15] Preparation of 5-(4
bromophenyl)pyrrolidin-2-one (2)
0
NH
Br
[518] Catalyst J (2.4 mg, 2 mol%) was used.
White solid (45mg, 94%); m.p. 147-149°C; 'H NMR (600 MHz,
PLUS International IP Law Firm Our ref. PCT2018-151
CDCl 3 ) 5 7.50 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 8.3 Hz, 2H),
6.00 (s, 1H), 4.72 (t, J = 7.1 Hz, 1H), 2.58 (dtd, J = 12.8,
8.4, 7.8, 4.9 Hz, 1H), 2.45 (ddp, J = 25.9, 17.2, 9.0 Hz,
2H), 1.93 (dt, J = 15.8, 8.1 Hz, 1H); 13 C NMR (150 MHz,
CDCl 3 ) 5 178.1, 141.5, 132.0, 127.3, 121.8, 57.4, 31.3,
30.0; IR (cm-1) 3175, 3074, 1677, 1262, 1008, 789; HRMS
(EI) m/z calcd. for CioHioBrNO [M]+: 238.9946, found:
238.9943.
[519] [Example 16] Preparation of 5-(4
fluorophenyl)pyrrolidin-2-one (3)
0
NH F
[520] Catalyst J (2.4 mg, 2 mol%) was used.
White solid (31 mg, 87%) ; m.p. 135-137°C; 'H NMR (600 MHz,
CDCl3) 5 7.26-7.21 (m, 2H), 7.10 (s, 1H), 7.05-6.98 (m, 2H),
4.72 (t, J = 7.1 Hz, 1H), 2.56-2.46 (m, 1H), 2.46-2.30 (m,
3 2H), 1.93-1.85 (m, 1H); 1 C NMR (150 MHz, CDCl3 ) 5 178.9,
162.4 (d, J = 246.1 Hz), 138.4 (d, J = 3.2 Hz), 127.4 (d, J
= 8.2 Hz), 115.8 (d, J = 21.6 Hz), 57.7, 31.4, 30.5; 19F
NMR (564 MHz, CDCl3) 5 -114.7 (m); IR (cm-1) 3167, 3084,
1682, 1509, 1217, 793, 482; HRMS (EI) m/z calcd. for
CioHioFNO [M]+: 179.0746, found: 179.0745.
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[521] [Example 17] Preparation of 5-(4
nitrophenyl)pyrrolidin-2-one (4)
0
NH
NO 2
[522] Catalyst J (2.4 mg, 2 mol%) was used.
White solid (35mg, 85%); m.p. 141-143°C; 1H NMR (600 MHz,
CDCl3) 5 8.24 (d, J = 8.6 Hz, 2H), 7.49 (d, J = 8.6 Hz, 2H),
6.75 (s, 1H), 4.89 (t, J = 7.2 Hz, 1H), 2.70-2.62 (m, 1H),
2.53-2.41 (m, 2H), 1.95 (dq, J = 15.7, 8.5 Hz, 1H); 13 C NMR
(150 MHz, CDCl 3 , one carbon merged to others) 5 149.9,
147.6, 126.4, 124.2, 57.4, 31.0, 30.2; IR (cm-1) 3067, 1678,
1520, 1338; HRMS (EI) m/z calcd. for CioHioN 20 3 [M]+:
206.0691, found: 206.0688.
[523] [Example 18] Preparation of 5-(4
methoxyphenyl)pyrrolidin-2-one (5)
0
NH
OMe
[524] Catalyst J (2.4 mg, 2 mol%) was used.
White solid (26mg, 68%); m.p. 128-130°C; 'H NMR (600 MHz,
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CDCl 3 ) 5 7.21 (d, J = 8.3 Hz, 2H), 6.89 (d, J = 8.2 Hz, 2H),
6.08 (s, 1H), 4.70 (t, J = 7.2 Hz, 1H), 3.80 (s, 3H), 2.56
3 2.34 (m, 3H), 1.95 (dq, J = 15.8, 8.3 Hz, 1H); 1 C NMR (150
MHz, CDCl,) 5 178.2, 159.3, 134.4, 126.9, 114.2, 57.6, 55.3,
31.6, 30.5; IR (cm-1) 3179, 2918, 1681, 1515, 1241, 1022;
HRMS (EI) m/z calcd. for CiiHi 3NO 2 [M]+: 191.0946, found:
191.0946.
[525] [Example 19] Preparation of tert-butyl {4-(5
oxopyrrolidin-2-yl)phenyl}carbamate (6)
0
NH
0 HN
[526] Catalyst J (11.8 mg, 10 mol%) and
NaBArF 4 (17.6 mg, 10 mol%) were used at 40°C for 12 hours
and further at 80°C for 36 hours. White solid (36 mg,
67%) ; m.p. 201-203°C; 1H NMR (400 MHz, CDCl 3 ) 5 7.36 (d, J
= 8.2 Hz, 2H), 7.21 (d, J = 8.6 Hz, 2H), 6.59 (s, 1H), 5.92
(s, 1H), 4.70 (t, J = 7.1 Hz, 1H), 2.59-2.50 (m, 1H), 2.49
3 2.34 (m, 2H), 2.00-1.88 (m, 1H), 1.51 (s, 9H); 1 C NMR (150
MHz, CDCl3) 5 178.2, 152.7, 138.2, 136.8, 126.3, 119.0,
80.7, 57.6, 31.5, 30.3, 28.3; IR (cm-1) 2968, 1782, 1746,
1718, 1271; HRMS (FAB) m/z calcd. for Ci 5 H2ON203 [M+H]+:
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277.1552, found: 277.1550.
[527] [Example 20] Preparation of 3,3-dimethyl-5
phenylpyrrolidin-2-one (7)
0
NH
[528] Catalyst J (11.8 mg, 10 mol%) and NaBArF4
(17.7 mg, 10 mol%) were used at 80°C. White solid (20mg,
53%) ; m.p. 161-163°C; 'H NMR (600 MHz, CDCl3) 5 7.37 (t, J
= 7.5 Hz, 2H), 7.31 (d, J = 7.5 Hz, 3H), 5.85 (s, 1H), 4.68
(t, J = 7.8 Hz, 1H), 2.38 (dd, J = 12.8, 6.9 Hz, 1H), 1.84
3 (dd, J = 12.8, 8.6 Hz, 1H), 1.26 (s, 3H), 1.22 (s, 3H); 1 C
NMR (150 MHz, CDCl3 ) o 182.6, 142.3, 128.9, 127.9, 125.7,
54.7, 47.4, 25.1, 24.5; IR (cm-1) 3169, 3076, 2968, 2924,
1677, 1260, 701; HRMS (EI) m/z calcd. for C1 2 Hi 5 NO [M]+:
189.1154, found: 189.1152.
[529] [Example 21] Preparation of 3-methyl-5
phenylpyrrolidin-2-one (8)
[530] Using Catalyst K (2.4 mg, 2 mol%). White solid (19
mg, 53%); 1H NMR spectroscopic analysis of the unpurified
reaction mixture represented 1:0.8 dr.
[531] cis-3-Methyl-5-phenylpyrrolidin-2-one (8-A)
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0
NH
[532] Major diastereomer: m.p. 101-103 0 C; 'H NMR
(600 MHz, CDC1 3 ) 5 7.40-7.34 (m, 2H), 7.33-7.28 (m, 3H),
5.85 (s, 1H), 4.69-4.59 (m, 1H), 2.77-2.66 (m, 1H), 2.65
2.52 (m, 1H), 1.66-1.55 (m, 1H), 1.25 (d, J = 7.0 Hz, 3H);
3 1 C NMR (150 MHz, CDCl3) 5 180.4, 142.2, 129.1, 128.2, 126.0,
56.6, 41.2, 37.3, 15.9; IR (cm-1) 3193, 2926, 1682, 1284,
758, 697, 482; HRMS (EI) m/z calcd. for C11Hi 3NO [M]+:
175.0997, found: 175.0996.
[533] trans-3-Methyl-5-phenylpyrrolidin-2-one (8-B)
O NH
[534] Minor diastereomer: m.p. 120-122°C; 'H NMR
(400 MHz, CDCl3) 5 7.40-7.33 (m, 2H), 7.33-7.25 (m, 3H),
6.00 (s, 1H), 4.77-4.69 (m, 1H), 2.70-2.54 (m, 1H), 2.31
2.15 (m, 2H), 1.25 (d, J = 7.2 Hz, 3H); 13 C NMR (100 MHz,
CDC1 3 ) 5 181.1, 142.8, 129.0, 127.9, 125.6, 55.7, 39.6,
34.9, 16.1; IR (cm-1) 3224, 2969, 1680, 1283, 737, 698;
HRMS (ESI) m/z calcd. for CiiHi 3NO [M+H]+: 176.1070, found:
176.1062.
PLUS International IP Law Firm Our ref. PCT2018-151
[535] [Example 22] Preparation of trans-4-methyl-5
phenylpyrrolidin-2-one (9)
0
NH
[536] Catalyst J (2.4 mg, 2 mol%) was used.
White solid (35mg, 99%) ; 'H NMR spectroscopic analysis of
the unpurified reaction mixture indicated >20:1 dr; m.p.
116-118°C; 1H NMR (600 MHz, CDCl3) 5 7.37 (t, J = 7.3 Hz,
2H), 7.34-7.29 (m, 3H), 5.90 (br, 1H), 4.22 (d, J= 7.3 Hz,
1H), 2.61 (dd, J = 16.7, 8.2 Hz, 1H), 2.30 (dp, J = 14.7,
6.8 Hz, 1H), 2.13 (dd, J = 16.7, 9.5 Hz, 1H), 1.16 (d, J =
3 6.7 Hz, 3H); 1 C NMR (150 MHz, CDCl 3 ) o 177.3, 141.0, 128.8,
128.1, 126.1, 65.9, 40.6, 38.8, 17.7; IR (cm-1) 3175, 2966,
1674, 1340, 751, 702; HRMS (EI) m/z calcd. for CiiHi 3NO
[M]+: 175.0997, found: 175.0995.
[537] [Example 23] Preparation of cis-3,3a,4,8b
tetrahydroindeno[1,2-b]pyrrol-2(1H)-one (10)
0
NH
[538] Catalyst J (2.4 mg, 2 mol%) was used.
White solid (34mg, 99%) ; 'H NMR spectroscopic analysis of
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the unpurified reaction mixture indicated >20:1 dr; m.p.
215-217°C; 1H NMR (600 MHz, CDCl 3 ) o 7.30-7.22 (m, 4H),
6.48 (br, 1H), 5.02 (d, J = 6.9 Hz, 1H), 3.35-3.27 (m, 2H),
2.90-2.83 (m, 1H), 2.71 (dd, J = 17.3, 9.2 Hz, 1H), 2.22
(dd, J = 17.4, 4.6 Hz, 1H); 13C NMR (150 MHz, CDCl,) 6 177.4,
142.5, 141.5, 128.7, 127.2, 125.4, 124.7, 63.2, 38.5, 37.6,
37.4; IR (cm-1) 3207, 1692, 1645, 748; HRMS (EI) m/z calcd.
for CiiHiiNO [M]+: 173.0841, found: 173.0842.
[539] [Example 24] Preparation of 3-methylisoindolin-1-one
(11)
0
| NH NH
[540] Using Catalyst K (5.9 mg, 5 mol%) and
NaBArF 4 (8.8 mg, 5 mol%). White solid (22mg, 75%); m.p.
114-116°C; 1H NMR (600 MHz, CDCl 3 ) 6 7.85 (d, J = 7.6 Hz,
1H), 7.58 (t, J = 7.9 Hz, 1H), 7.47 (t, J = 7.5 Hz, 1H),
7.43 (d, J = 8.0 Hz, 1H), 6.75 (s, 1H), 4.70 (q, J = 6.8 Hz,
1H), 1.51 (d, J = 6.7 Hz, 3H); 1 3 C NMR (150 MHz, CDCl 3 ) 6
170.5, 148.8, 131.9, 131.4, 128.1, 123.8, 122.2, 52.4,
20.3; IR (cm-1) 3219, 1693, 1655, 721, 682; HRMS (EI) m/z
calcd. for C9 H 9NO [M]+: 147.0684, found: 147.0685.
[541] [Example 25] Preparation of 3-phenylisoindolin-1-one
(12)
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0
| NH
[542] Catalyst J (5. 9 mg, 5 mol%) and NaBArF4
(8.8 mg, 5 mol%) were used. White solid (37 mg, 88%); m.p.
216-218°C; 'H NMR (600 MHz, CDCl3) 5 7.89 (d, J = 7.3 Hz,
1H), 7.49 (dt, J = 21.2, 7.3 Hz, 2H), 7.38-7.31 (m, 3H),
7.28-7.25 (m, 2H), 7.23 (d, J = 7.4 Hz, 1H), 6.63 (s, 1H),
3 5.62 (s, 1H); 1 C NMR (150 MHz, CDCl3) 5 170.9, 147.9, 138.4,
132.3, 130.7, 129.1, 128.5, 128.3, 126.8, 123.8, 123.3,
60.7; IR (cm-1) 3172, 3055, 2855, 1680, 740, 695; HRMS (EI)
m/z calcd. for C1 4 HiiNO [M]+: 209.0841, found: 209.0842.
[543] [Example 26] Preparation of 5-(benzofuran-2
yl)pyrrolidin-2-one (13)
0
NH
/0O
[544] Catalyst J (11.8 mg, 10 mol%) and NaBArF4
(17.7 mg, 10 mol%) were used. White solid (37mg, 92%); m.p.
122-124°C; 'H NMR (600 MHz, CDCl3) 5 7.53 (d, J = 7.7 Hz,
1H), 7.45 (d, J = 8.2 Hz, 1H), 7.30-7.26 (m, 1H), 7.23 (t,
J = 7.5 Hz, 1H), 6.61 (s, 1H), 6.30 (s, 1H), 4.91 (dd, J =
PLUS International IP Law Firm Our ref. PCT2018-151
7.6, 4.7 Hz, 1H), 2.62-2.54 (m, 2H), 2.46-2.39 (m, 1H),
3 2.38-2.31 (m, 1H); 1 C NMR (150 MHz, CDCl 3 ) o 178.0, 157.1,
155.0, 127.8, 124.5, 123.0, 121.0, 111.2, 102.8, 51.7, 29.3,
26.9; IR (cm-1) 3193, 3072, 1688, 1257, 812, 743; HRMS (EI)
m/z calcd. for C1 2 HiiNO 2 [M]+: 201.0790, found: 201.0790.
[545] [Example 27] Preparation of 5-(thiophen-2
yl)pyrrolidin-2-one (14)
0
NH
[546] Catalyst J (11.8 mg, 10 mol%) and NaBArF4
(17.7 mg, 10 mol%) were used at 80°C. White solid (28mg,
84%); m.p. 112-114°C; 'H NMR (600 MHz, CDCl 3 ) 5 7.30-7.22
(m, 1H), 7.02-6.94 (m, 2H), 6.32 (s, 1H), 5.03 (t, J = 6.8
Hz, 1H), 2.66-2.48 (m, 2H), 2.48-2.35 (m, 1H), 2.20-2.08 (m,
3 1H); 1 C NMR (150 MHz, CDCl3) 5 177.7, 146.4, 126.9, 124.8,
124.1, 53.8, 31.7, 30.0; IR (cm-1) 3165, 3069, 1677, 1260,
784, 698, 481; HRMS (EI) m/z calcd. for CeH9 NOS [M]+:
167.0405, found: 167.0404.
[547] [Example 28] Preparation of 5,5-dimethylpyrrolidin-2
one (15)
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O NNH
[548] Catalyst J (2.4 mg, 2 mol%) was used. White
solid (20mg, 88%); 1H NMR (600 MHz, CDCl 3 ) 5 6.35 (s, 1H),
2.40 (t, J = 7.9 Hz, 2H), 1.91 (t, J = 7.9 Hz, 2H), 1.28 (s,
3 6H); 1 C NMR (150 MHz, CDCl 3 ) 5 177.0, 56.5, 35.3, 30.6,
29.2.
[549] [Example 29] Preparation of 1-azaspiro[4.5]decan-2
one (16)
0
NH
[550] Catalyst J (2.4 mg, 2 mol%) was used. White solid (23mg, 75%); m.p. 126-128°C; 'H NMR (600 MHz, CDCl 3
) 6.56 (s, 1H), 2.37 (t, J = 8.1 Hz, 2H), 1.90 (t, J = 8.1
3 Hz, 2H), 1.57-1.48 (m, 8H), 1.44-1.38 (m, 2H); 1 C NMR (150
MHz, CDCl3) 5 177.1, 59.2, 38.3, 32.7, 29.8, 25.1, 23.0; IR
(cm-1) 3209, 2929, 1683, 1264, 731, 701; HRMS (EI) m/z
calcd. for C9 Hi 5 NO [M]+: 153.1154, found: 153.1156.
[551] [Example 30] Preparation of 3,3-dimethylisoindolin-1
one (17)
PLUS International IP Law Firm Our ref. PCT2018-151
0
| NH
[552] Prepared with Catalyst J (5.9 mg, 5
mol%) and NaBArF 4 (8.8 mg, 5 mol%) . White solid (30mg,
94%); m.p. 160-162°C; 1H NMR (600 MHz, CDCl 3 ) 5 7.82 (d, J
= 7.6 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.44 (t, J = 7.5
Hz, 1H), 7.40 (d, J = 7.7 Hz, 1H), 7.01 (s, 1H), 1.56 (s,
3 6H); 1 C NMR (150 MHz, CDCl 3 ) 5 169.6, 153.0, 132.0, 130.6,
128.0, 123.8, 120.8, 59.0, 27.8; IR (cm-1) 3199, 2967, 1689,
1264, 732; HRMS (EI) m/z calcd. for CioH11NO [M]+: 161.0841,
found: 161.0839.
[553] [Example 31] Preparation of (R)-5-ethyl-5
methylpyrrolidin-2-one (18)
0
NH
[554] Catalyst J (2.4 mg, 2 mol%) was used.
Colorless oil (21 mg, 83%); 1H NMR (400 MHz, CDCl3) 5 6.86
(s, 1H), 2.44-2.28 (m, 2H), 1.93 (ddd, J = 12.8, 8.9, 7.3
Hz, 1H), 1.80 (ddd, J= 12.9, 9.2, 7.0 Hz, 1H), 1.57-1.46
(m, 2H), 1.21 (s, 3H), 0.89 (t, J = 7.5 Hz, 3H); 13C NMR
(100 MHz, CDCl3) 5 177.5, 59.6, 34.6, 32.9, 30.6, 26.7,
8.4; IR (cm-1) 3207, 2965, 1683, 1380; HRMS (FAB) m/z calcd.
forC7Hi3NO [M+H]+: 128.1075, found: 128.1077; Optical
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Rotation: [a]D = -11.8 (c = 1.0, benzene).
[555] [Example 32] Preparation of 5-methylpyrrolidin-2-one
(19)
O NH
[556] Using Catalyst K (5.9 mg, 5 mol%) and
NaBArF 4 (8.8 mg, 5 mol%). 'H NMR (400 MHz, CDCl 3 ) 5 6.37 (s,
1H), 3.78 (q, J = 6.4 Hz, 1H), 2.41-2.20 (m, 3H), 1.72-1.59
(m, 1H), 1.22 (d, J = 6.2 Hz, 3H); 13 C NMR (150 MHz, CDCl3)
178.1, 50.0, 30.5, 29.2, 22.2.
[557] [Example 33] Preparation of cis
hexahydrocyclopenta[b]pyrrol-2(1H)-one (20)
O NH
[558] Using Catalyst K (5.9 mg, 5 mol%) and
NaBArF 4 (8.8 mg, 5 mol%). White solid (18mg, 72%); 1H NMR
spectroscopic analysis of the unpurified reaction mixture
indicated >20:1 dr; m.p. 53-55°C; 1H NMR (600 MHz, CDCl 3 ) 5
5.87 (s, 1H), 4.14-4.04 (m, 1H), 2.83 (q, J = 8.3, 7.7 Hz,
1H), 2.63 (dd, J = 17.6, 10.3 Hz, 1H), 2.11-2.00 (m, 1H),
1.79 (dt, J = 13.9, 7.8 Hz, 1H), 1.72-1.60 (m, 4H), 1.56
3 1.48 (m, 1H); 1 C NMR (150 MHz, CDCl 3 ) 5 178.1, 59.1, 37.8,
37.3, 34.5, 34.3, 23.7; IR (cm-1) 3221, 2953, 1683, 730;
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HRMS (EI) m/z calcd. for C7 HiiNO [M]+: 125.0841, found:
125.0842.
[559] [Example 34] Preparation of octahydro-3a,7:5,9
dimethanocycloocta[b]pyrrol-2(3H)-one (21)
O NNH
[560] Using Catalyst K (5.9 mg, 5 mol%) and NaBArF 4 (8.8 mg, 5 mol%). White solid (35mg, 91%); m.p.
161-163°C; 1H NMR (600 MHz, CDCl3) 5 5.70 (s, 1H), 3.47 (s,
1H), 2.11-2.01 (m, 3H), 1.93-1.87 (m, 3H), 1.84 (d, J =
11.9 Hz, 2H), 1.80 (d, J = 12.8 Hz, 1H), 1.76-1.70 (m, 3H),
1.67 (d, J = 12.4 Hz, 1H), 1.61 (d, J = 12.7 Hz, 1H), 1.42
3 (d, J = 11. 4 Hz, 1H) ; 1 C NMR (150 MHz, CDCl 3 ) 5 178. 9, 63. 9,
46.2, 40.0, 38.5, 37.1, 37.0, 36.7, 29.5, 29.4, 28.9, 27.3;
IR (cm-1) 3172, 2910, 2851, 1682, 733; HRMS (EI) m/z calcd.
for C12H1 7 NO [M]+: 191.1310, found: 191.1307.
[561] [Example 35] Preparation of 4,4-dimethylpyrrolidin-2
one (22)
0
NH
[562] Using Catalyst K (5.9 mg, 5 mol%) and
NaBArF 4 (8.8 mg, 5 mol%) in a solvent of hexafluoro-2
propanol (2.4 mL). Yellowish oil (7 mg, 31%); 1H NMR (600
MHz, CDCl3) 5 6.04 (s, 1H), 3.11 (s, 2H), 2.14 (s, 2H),
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3 1.17 (s, 6H); 1 C NMR (150 MHz, CDCl 3 ) 5 178.0, 55.4, 45.2,
35.9, 27.7; IR (cm-1) 3233, 2956, 2868, 1686, 1311, 1249;
HRMS (FAB) m/z calcd. for C6HiiNO [M+H]+: 114.0919, found:
114.0917.
[563] [Example 36] Preparation of 5-vinylpyrrolidin-2-one
(23)
0
NH
[564] Using Catalyst K (11.8 mg, 10 mol%) and
NaBArF (17.7 mg, 10 mol%). Colorless resin (14mg, 63%); 1H
NMR (600 MHz, CDCl 3 ) 5 6.40 (s, 1H), 5.79 (ddd, J = 16.9,
10.2, 6.6 Hz, 1H), 5.21 (dd, J = 16.9, 1.3 Hz, 1H), 5.11
(dd, J = 10.3, 1.4 Hz, 1H), 4.15 (q, J = 6.6 Hz, 1H), 2.42
2.26 (m, 3H), 1.88-1.77 (m, 1H); 13 C NMR (150 MHz, CDCl3 ) 5
178.4, 138.7, 115.7, 56.7, 29.8, 28.0.
[565] [Example 37] Preparation of 5-(1
phenylvinyl)pyrrolidin-2-one (24)
0
NH
[566] Catalyst J (11.8 mg, 10 mol%) and
NaBArF 4 (17.7 mg, 10 mol%) were used. White solid (18mg,
48%); m.p. 104-106°C; 'H NMR (600 MHz, CDCl3) 5 7.37-7.30
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(m, 5H), 6.56 (s, 1H), 5.35 (s, 1H), 5.28 (s, 1H), 4.70 (t,
J = 6.0 Hz, 1H), 2.42-2.29 (m, 3H), 1.84 (tt, J = 10.2, 5.6
3 Hz, 1H); 1 C NMR (150 MHz, CDCl3) 5 178.6, 149.1, 138.9,
128.6, 128.0, 126.5, 111.5, 56.7, 29.4, 27.8; IR (cm-1)
3203, 1684, 766, 700; HRMS (EI) m/z calcd. for C 12 H 13NO
[M]+: 187.0997, found: 187.0996.
[567] [Example 38] Preparation of (E)-5-Styrylpyrrolidin-2
one (25)
0
NH
[568] Catalyst J (11.8 mg, 10 mol%) and NaBArF4
(17.7 mg, 10 mol%) were used. White solid (33mg, 88%); m.p.
101-103 0 C; 1H NMR (400 MHz, CDCl 3 ) 5 7.39-7.30 (m, 4H),
7.27 (t, J = 7.4 Hz, 1H), 6.55 (d, J = 15.8 Hz, 1H), 6.13
(dd, J = 15.8, 7.4 Hz, 1H), 5.87 (s, 1H), 4.40-4.28 (m, 1H),
3 2.47-2.32 (m, 3H), 2.01-1.87 (m, 1H); 1 C NMR (150 MHz,
CDCl 3 ) 5 178.0, 136.0, 131.2, 129.8, 128.7, 128.0, 126.5,
56.4, 29.9, 28.5; IR (cm-1) 3214, 3024, 1684, 965, 749,
692; HRMS (EI) m/z calcd. for C1 2 H1 3 NO [M]+: 187.0997,
found: 187.0995.
[569] [Example 39] Preparation of 5
(phenylethynyl)pyrrolidin-2-one (26)
PLUS International IP Law Firm Our ref. PCT2018-151
0
NH
[570] Catalyst J (11.8 mg, 10 mol%) and NaBArF4
(17.7 mg, 10 mol%) were used. White solid (34mg, 92%); m.p.
99-101°C; 'H NMR (600 MHz, CDCl,) 5 7.41 (dd, J = 7.7, 1.7
Hz, 2H), 7.34-7.29 (m, 3H), 5.84 (s, 1H), 4.62 (dd, J = 7.5,
5.1 Hz, 1H), 2.57-2.50 (m, 2H), 2.40-2.34 (m, 1H), 2.34
3 2.27 (m, 1H); 1 C NMR (150 MHz, CDCl3 ) 5 177.3, 131.6, 128.6,
128.3, 122.1, 87.8, 84.1, 45.2, 29.4, 29.2; IR (cm-1) 3176,
3066, 1693, 1335, 1257, 754; HRMS (EI) m/z calcd. for
C1 2 HiNO [M]+: 185.0841, found: 185.0838.
[571] [Example 40] Preparation of 5-(3-phenylprop-1-yn-1
yl)pyrrolidin-2-one (27)
0
NH
[572] Catalyst J (11.8 mg, 10 mol%) and NaBArF4 (17.7 mg, 10 mol%) were used. Yellow resin (30 mg, 75%);
1H NMR (600 MHz, CDCl 3 ) 5 7.35-7.26 (m, 4H), 7.27-7.20 (m,
1H), 6.59 (s, 1H), 4.46-4.34 (m, 1H), 3.58 (s, 2H), 2.49
PLUS International IP Law Firm Our ref. PCT2018-151
3 2.36 (m, 2H), 2.34-2.24 (m, 1H), 2.20-2.11 (m, 1H); 1 C NMR
(150 MHz, CDCl 3 ) 5 177.9, 136.3, 128.7, 127.9, 126.8, 82.2,
81.4, 45.2, 29.7, 29.4, 25.1; IR (cm-1) 3229, 3028, 1685,
1257, 1177, 698; HRMS (ESI) m/z calcd. for C1 3 H 1 3 NO [M+H]+:
200.1070, found: 200.1066.
[573] [Example 41] Preparation of 5-(prop-1-yn-1
yl)pyrrolidin-2-one (28)
0
NH
[574] Catalyst J (11.8 mg, 10 mol%) and NaBArF4
(17.7 mg, 10 mol%) were used. White solid (15 mg, 61%);m.p.
77-79°C; 'H NMR (600 MHz, CDCl 3 ) o 6.23 (s, 1H), 4.36-4.28
(m, 1H), 2.49-2.34 (m, 2H), 2.34-2.24 (m, 1H), 2.16-2.06 (m,
3 1H), 1.80 (s, 3H); 1 C NMR (150 MHz, CDCl 3 ) 5 177.8, 80.4,
78.3, 45.2, 29.7, 29.4, 3.6; IR (cm-1) 3165, 3075, 1688,
1257, 777, 675, 495; HRMS (EI) m/z calcd. for C 7H9NO [M]+:
123.0684, found: 123.0685.
[575] [Example 42] Preparation of trans-4-Ethyl-5
phenylpyrrolidin-2-one (29)
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0
NH
[576] Catalyst J (2.4 mg, 2 mol%) was used.
White solid (34 mg, 90%); >20:1 d.r. and 12.6:1 r.r. were
confirmed by 1H NMR spectroscopy; m.p. 131-133°C; 1H NMR
(400 MHz, CDCl 3 ) 6 7.39-7.32 (m, 2H), 7.32-7.27 (m, 3H),
6.46 (s, 1H), 4.28 (d, J= 6.7 Hz, 1H), 2.69-2.49 (m, 1H),
2.17-2.06 (m, 2H), 1.74-1.58 (m, 1H), 1.50-1.35 (m, 1H),
0.89 (t, J = 7.4 Hz, 3H); 1 3C NMR (100 MHz, CDCl 3 ) 5 177.6,
141.6, 128.7, 127.9, 126.2, 64.1, 47.0, 36.4, 26.0, 11.9;
IR (cm-1) 3211, 2959, 1690, 1455, 1282, 755, 699; HRMS
(FAB) m/z calcd. for C1 2Hi 5NO [M+H]+: 190.1232, found:
190.1230.
[577] [Example 43] Preparation of 4-benzyl-5,5
dimethylpyrrolidin-2-one (30-A)/trans-4-Isopropyl-5
phenylpyrrolidin-2-one (30-B)
[578] Catalyst J (2.4 mg, 2 mol%) was used. Combined
isolated yield: 96% (39 mg). 1.3:1 r.r was confirmed by 'H
NMR spectroscopy.
[579] 4-Benzyl-5,5-dimethylpyrrolidin-2-one (30-A)
PLUS International IP Law Firm Our ref. PCT2018-151
0
NH
[580] Major regioisomer: White solid (22
mg); m.p. 124-126°C; 1H NMR (400 MHz, CDCl 3 ) 5 7.29 (t, J =
7.4 Hz, 2H), 7.21 (t, J = 7.3 Hz, 1H), 7.16 (d, J = 7.2 Hz,
2H), 6.66 (s, 1H), 2.81 (dd, J = 13.3, 4.6 Hz, 1H), 2.52
(dd, J= 13.2, 10.6 Hz, 1H), 2.43-2.33 (m, 1H), 2.28-2.12
(m, 2H), 1.26 (s, 3H), 1.22 (s, 3H); 13C NMR (150 MHz,
CDCl3) 5 176.0, 139.7, 128.6, 128.6, 126.3, 58.8, 47.5,
36.5, 35.9, 28.4, 23.5; IR (cm-1) 3217, 2966, 1691; HRMS
(FAB) m/z calcd. for C13H1 7NO [M+H]+: 204.1388, found:
204.1387.
[581] trans-4-Isopropyl-5-phenylpyrrolidin-2-one (30-B)
0
NH
[582] Minor regioisomer: Colorless oil (17
mg); >20:1 d.r. was confirmed by 1H NMR spectroscopy; 'H
NMR (400 MHz, CDCl 3 ) 5 7.43-7.33 (m, 2H), 7.32-7.26 (m, 3H),
6.17 (s, 1H), 4.43 (d, J = 5.7 Hz, 1H), 2.55-2.44 (m, 1H),
2.25-2.16 (m, 2H), 1.85-1.75 (m, 1H), 0.96 (d, J = 6.7 Hz,
3H), 0.86 (d, J = 6.8 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) 5
177.4, 142.4, 128.8, 127.9, 126.4, 61.7, 50.8, 33.0, 30.1,
PLUS International IP Law Firm Our ref. PCT2018-151
20.8, 18.8; IR (cm-1) 3209, 2957, 1694, 700; HRMS (FAB) m/z
calcd. for C13H1 7 NO [M+H]+: 204.1388, found: 204.1389.
[583] [Example 44] Preparation of (S)-2-(5,5-dimethyl-2
oxopyrrolidin-3-yl)isoindoline-1,3-dione (31)
0N,. O NH
[584] Using Catalyst K (5.9 mg, 5 mol%)
and NaBArF 4 (8.8 mg, 5 mol%). White solid (29 mg, 56%); m.p.
217-219°C; 1H NMR (400 MHz, CDCl 3 ) 5 7.85 (dd, J = 5.4, 3.1
Hz, 2H), 7.72 (dd, J = 5.5, 3.1 Hz, 2H), 5.86 (s, 1H),
5.13-5.05 (m, 1H), 2.44 (t, J = 11.6 Hz, 1H), 2.33 (dd, J =
3 12.4, 9.3 Hz, 1H), 1.47 (s, 3H), 1.38 (s, 3H); 1 C NMR (150
MHz, CDCl3 ) 5 170.6, 167.5, 134.1, 131.9, 123.5, 53.6, 49.7,
39.5, 29.9, 29.3; IR (cm-1) 3180, 3087, 1701, 1387, 716;
HRMS (EI) m/z calcd. for Ci 4 Hi 4 N203 [M]+: 258.1004, found:
28 258.1007; Optical Rotation: [a] D = -60 (c = 1.0, CHCl3);
HPLC Analysis (250 mm CHIRALPAK AD-H column, 20% i
PrOH/hexanes, 0.8 mL/min, 254 nm, 25 0 C) indicated 99% ee:tR
(major) = 35.2 min, tR (minor) = 11.1 min.
[585] [Example 45] Preparation of 2-((3S,5S)-2-oxo-5
phenylpyrrolidin-3-yl)isoindoline-1,3-dione (32)
PLUS International IP Law Firm Ourref.PCT2018-151
0
N, 0 N
[586] Using Catalyst K (5.9 mg, 5 mol%)
and NaBArF 4 (8.8 mg, 5 mol%). White solid (29 mg, 48%); 1H
NMR spectroscopic analysis of the unpurified reaction
mixture indicated 10:1 dr; m.p. 260-262°C; 1H NMR (600 MHz,
CDCl3) 5 7.89-7.81 (m, 2H), 7.76-7.70 (m, 2H), 7.53 (d, J =
7.4 Hz, 2H), 7.41 (t, J = 7.6 Hz, 2H), 7.34 (t, J = 7.5 Hz,
1H), 6.28 (s, 1H), 5.09 (t, J = 10.3 Hz, 1H), 4.74 (t, J =
3 8.1 Hz, 1H), 2.90-2.80 (m, 1H), 2.61-2.45 (m, 1H); 1 C NMR
(150 MHz, CDCl 3 ) 5 172.0, 167.6, 141.2, 134.4, 132.1, 129.2,
128.7, 126.8, 123.7, 55.2, 50.2, 36.3; IR (cm-1) 3356, 2923,
1710, 1390, 718; HRMS (EI) m/z calcd. for C 1 8 H1 4N 2 0 3 [M]+:
28 306.1004, found: 306.1007; Optical Rotation: [a] D= -34 (c
= 1.0, CHC13); HPLC Analysis (250 mm CHIRALPAK AD-H column,
% i-PrOH/hexanes, 0.8 mL/min, 254 nm, 25°C) indicated 98%
ee: tR (major) = 41.8 min, tR (minor) = 27.7 min.
[587] [Example 46] Preparation of (R)-2-(2,2-dimethyl-5
oxopyrrolidin-3-yl)isoindoline-1,3-dione (33)
PLUS International IP Law Firm Our ref. PCT2018-151
0
0 NH N'
[588] Using Catalyst K (5.9 mg, 5 mol%)
and NaBArF 4 (8.8 mg, 5 mol%). White solid (28 mg, 55%); m.p.
172-174°C; 1H NMR (600 MHz, CDCl 3 ) 5 7.85 (dd, J = 5.5, 3.1
Hz, 2H), 7.74 (dd, J = 5.5, 3.1 Hz, 2H), 6.84 (s, 1H), 4.73
(dd, J = 9.4, 5.9 Hz, 1H), 3.32 (dd, J = 17.2, 5.9 Hz, 1H),
2.75 (dd, J = 17.2, 9.4 Hz, 1H), 1.42 (s, 3H), 1.20 (s,
3 3H); 1 C NMR (150 MHz, CDCl3 ) 5 174.2, 168.4, 134.5, 131.6,
123.7, 60.2, 55.3, 33.0, 29.6, 24.1; IR (cm-1) 2962, 1830,
1710, 1371, 712; HRMS (EI) m/z calcd. for C1 4 H1 4 N 2 0 3 [M]+:
258.1004, found: 258.1005; Optical Rotation: [a]28 D = 33 (c
= 1.0, CHCl3); HPLC Analysis (250 mm CHIRALCELOD-Hcolumn,
% i-PrOH/hexanes, 0.8 mL/min, 254 nm, 25°C) indicated 99%
ee: tR (major) = 31.0 min,tR (minor) = 24.8 min.
[589] [Example 47] Preparation of 2-((2-oxooctahydro-3aH
indol-3a-yl)methyl)isoindoline-1,3-dione (34)
0 14N 0 Q~N NH
[590] Using Catalyst K (5.9 mg, 5 mol%)
and NaBArF 4 (8.8 mg, 5 mol%). White solid (53 mg, 88%); m.p.
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174-176°C; 1H NMR (400 MHz, CDCl3) 5 7.86 (dd, J = 5.5, 3.1,
2H), 7.75 (dd, J = 5.5, 3.1Hz, 2H), 5.52 (s, 1H), 3.79 (d,
J = 0.8 Hz, 2H), 3.58 (t, J = 4.0 Hz, 1H), 2.48 (d, J =
16.4, 1H), 2.03 (d, J = 16.4 Hz, 1H), 1.94-1.82 (m, 1H),
1.72-1.64 (m, 1H), 1.60-1.42 (m, 6H); 13 C NMR (100 MHz,
CDCl 3 ) 5 176.7, 169.0, 134.4, 131.9, 123.7, 55.5, 43.2,
43.1, 42.6, 30.8, 26.5, 21.2, 20.0; IR (cm-1) 3218, 2931,
1772, 1708, 1394, 724; HRMS (EI) m/z calcd. for C1 7 HisN2 03
[M]+: 298.1317, found: 298.1318.
[591] [Example 48] Preparation of cis-tert-butyl {(2
oxooctahydro-3aH-indol-3a-yl)methyl}carbamate (35)
H 0 N
[592] Using Catalyst K(5.9 mg, 5 mol%)
and NaBArF 4 (8.8 mg, 5 mol%) in a solvent of hexafluoro-2
propanol (2.4 mL); Beige solid (24 mg, 45%); m.p. 62-64°C;
1H NMR (400 MHz, CDCl3) 55.96 (s, 1H), 4.72 (s, 1H), 3.46
(t, J = 3.8 Hz, 1H), 3.31-3.09 (m, 2H), 2.24 (d, J= 16.2
Hz, 1H), 1.99 (d, J = 16.2 Hz, 1H), 1.76-1.54 (m, 2H),
1.53-1.34 (m, 15H); 13C NMR (100 MHz, CDCl,) 5177.0, 156.2,
79.6, 55.3, 45.0, 42.4, 42.0, 30.0, 28.3, 26.8, 21.0, 20.0;
IR (cm-1) 3279, 2929, 1681, 1526, 1365, 1249, 1166, 1008,
918, 730; HRMS (FAB) m/z calcd. for Ci 4H 2 4N 2 0 3 [M+H]+:
269.1865, found: 269.1862.
PLUS International IP Law Firm Our ref. PCT2018-151
[593] [Example 49] Preparation of tert-butyl 2-methyl-5
oxopyrrolidine-1-carboxylate (36)
[594] 5-Methylpyrrolidin-2-one was separated by one-pot
Boc-protection and then prepared.
[595] The catalytic reaction mixture of 3-butyl-1,4,2
dioxazol-5-one was cooled to room temperature, di-tert
butyl dicarbonate (Boc20, 91.9 pL 0.4 mmol), 4
(dimethylamino)pyridine (DMAP, 24.4 mg, 0.2 mmol), and
triethylamine (27.8 pL, 0.2 mmol) were added thereto and
the mixture was vigorously stirred at room temperature for
12 hours. The reaction mixture was filtered with celite,
washed with dichloromethane (10 mL x 4), and concentrated
under reduced pressure to obtain a residue, which was
separated and purified by column chromatography (eluent: n
hexane/EtOAc, 2:1 - 1:2) to obtain the desired compound.
[596] The compound prepared by the above method is shown in
the following.
O
NBoc
[597] Yellowish oil (22mg, 55%); 1H NMR (600 MHz,
CDCl 3 ) o 4.28-4.18 (m, 1H), 2.60 (dt, J = 19.8, 10.0 Hz,
1H), 2.42 (ddd, J = 17.6, 9.4, 2.7 Hz, 1H), 2.16 (dt, J =
20.6, 9.9 Hz, 1H), 1.66-1.61 (m, 1H), 1.52 (s, 9H), 1.31 (d,
3 J = 6.3 Hz, 3H); 1 C NMR (150 MHz, CDCl3) 5 174.2, 149.9,
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82.6, 54.0, 31.3 28.0, 25.2, 20.2.
[598] [Examples 50 to 58, and Comparative Examples 3 to 7]
Preparation of gamma-lactam compound
O Catalyst (X mol %) O O4 NaBArF 4 (X moI %) CN
+ O N + Ph Ph N DCM-d 2 , T, Time 1 Ph 1-a
r Nh r r N OMe N OMe C/ N e),-~ / 1Boc--70M Z 0 Ph Z 0 16 0 F 3 C"' 0 D E F G
Kr NIrIr, MeO r MeM Nr Me N Me ArsC1 r C1 0 N 0 MeG" K MeO L A B
[599]
[600] A gamma-lactam compound was prepared in the same
manner as in Example 19, except that the catalyst and time
were different as shown in Table 1, and the results are
shown in Table 1.
[601] [Table 1] Reaction Yield (%) of Yield of Mole Catalyst NaBArF4 temperat Reaction gamma-lactam Compound ratio of (mol%) (mol%) ure, T time (h) 1-a 1:1-a (° compound (1)
Example Complex D NaBArF4 rt 18 73 14 5.2:1 50 (10 mol%) (10 mol%)
Example Complex E NaBArF4 rt 18 81 17 4.8:1 51 (10 mol%) (10 mol%)
Example Complex F NaBAr4 rt 12 86 13 6.2:1
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52 (10 mol%) (10 mol%)
Example Complex G NaBArF4 rt 12 90 9 9.8:1 53 (10 mol%) (10 mol%)
Example Complex I NaBArF4 rt 24 80 8 9.5:1 54 (10 mol%) (10 mol%)
Example Complex J NaBArF4 rt 2 97 <5 >20:1 55 (10 mol%) (10 mol%)
Example Complex K NaBArF4 rt 6 98 <5 >20:1 56 (10 mol%) (10 mol%)
Example Complex L NaBArF 4 rt 6 98 <5 >20:1 57 (10 mol%) (10 mol%)
Example Complex J NaBArF4 rt 12 94 <5 >20:1 58 (2 mol%) (2 mol%)
Compara
tive Complex A NaBArF4 60 12 39 17 2.3:1 Example (10 mol%) (10 mol%)
3
Compara
tive Complex B NaBArF4 40 18 73 15 4.8:1 Example (10 mol%) (10 mol%)
4
Compara
tive Rh 2 (OAc) 4b - 40 12 <5 <5 Example (5 mol%)
5
Compara
tive Rh 2 (esp) 2D - 40 12 <5 <5 Example (5 mol%)
6
Compara
tive Ru(TPP)COb NaBArF4 40 12 <5 35 Example (5 mol%) (5 mol%)
7
rt: room temperature, b The catalyst of Comparative Example 5-7 was purchased
PLUS International IP Law Firm Our ref. PCT2018-151
from Aldrich and TCl.
[602] As shown in Table 1 above, the catalyst which is the
metal complex having a specific ligand of the present
invention produced a lactam compound with surprisingly
excellent selectivity and yield as compared with the
catalysts of Comparative Examples 3 to 7.
[603] Furthermore, with the metal catalyst of the present
invention, the reaction is performed under mild conditions
and simultaneously, a gamma-lactam compound may be obtained
with a high yield and excellent selectivity, and the method
of preparing a gamma-lactam compound of the present
invention may be very usefully applied to a raw material
and an intermediate such as various natural products and
medicines.
[604] Example III: Application of method of preparing
gamma-lactam compound of the present invention
[605] [Example 59] Preparation of (Z)-6a-(pent-2-en-1
yl)hexahydrocyclopenta[b]pyrrole-2,6-dione
O< O, 10 mo% J 0 IN 10 mol% NaBArF 4 0 DCM,40°Cto80°C HN Hb Ha He
[606] 0
[607] (Z)-6a-(Pent-2-en-1-yl)hexahydrocyclopenta[b]pyrrole
2,6-dione was prepared in the same manner as in Example 19,
except that the starting material was different.
PLUS International IP Law Firm Our ref. PCT2018-151
0
NH
0
[608] Preparation was performed by
stirring at 40'C for 12 hours and stirring again at 80°C
for 12 hours, using Catalyst J (11.8 mg, 10 mol%) and
NaBArF4 (17.7 mg, 10 mol%). Colorless oil (29mg, 70%); 1H
NMR (400 MHz, CDCl 3 ) 5 5.69 (s, 1H), 5.62 (dt, J = 10.9,
7.4 Hz, 1H), 5.35-5.18 (m, 1H), 2.82-2.62 (m, 2H), 2.52
(ddd, J = 18.1, 8.1, 4.5 Hz, 1H), 2.41-2.15 (m, 5H), 2.05
(p, J = 7.7 Hz, 2H), 1.76-1.63 (m, 1H), 0.97 (t, J = 7.5 Hz,
3 3H); 1 C NMR (150 MHz, CDCl 3 ) 5 214.9, 175.8, 137.2, 120.2,
67.9, 38.9, 37.2, 36.9, 32.2, 26.0, 20.7, 14.0; IR (cm-1)
3214, 2961, 2932, 2872, 1739, 1686; HRMS (EI) m/z calcd.
for C12 Hi 7 N0 2 [M]+: 207.1259, found: 207.1258.
[609] [Example 60] Preparation of (5S)-5
((3R,5R,9S,10S,13S,14S)-3-methoxy-10,13
dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-5
methylpyrrolidin-2-one
0
-. O 5 mol% K HN Me (R) O ' 5 mol% NaBArF 4 Me -,(S) Me DCM,rt Me
MeO* H MeO'
[6101] H
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0
HN Me
Me
MeO" H
[611] Prepared with Catalyst K (5.9 mg, 5 mol%) and NaBArF 4 (8.8 mg, 5 mol%). White solid (26
mg, 32%); m.p. 231-233°C; 'H NMR (600 MHz, CDCl,) 5 5.57 (s,
1H), 3.35 (s, 3H), 3.16 (tt, J = 10.5, 4.6 Hz, 1H), 2.37
(dt, J = 18.1, 8.8 Hz, 1H), 2.31-2.21 (m, 1H), 2.12-1.98 (m,
2H), 1.90-1.81 (m, 1H), 1.80-1.54 (m, 10H), 1.36 (d, J =
21.9 Hz, 7H), 1.29-1.16 (m, 4H), 1.14-1.02 (m, 3H), 0.98
0.85 (m, 4H), 0.73 (s, 3H); 13 C NMR (150 MHz, CDCl 3 , one
carbon merged to others) 5 177.6, 80.3, 61.7, 59.6, 56.3,
55.6, 43.5, 41.9, 40.2, 35.3, 35.2, 34.8, 34.8, 32.7, 29.1,
28.7, 27.2, 26.8, 26.2, 23.7, 23.3, 23.0, 20.5, 13.6; IR
(cm-1) 3230, 2925, 2862, 1689, 1448, 1369, 1098; HRMS (EI)
m/z calcd. for C2 5 H 4 1NO2 [M]+: 387.3137, found: 387.3139.
[612] [Example 61] Preparation of (±)-trans-4-Methyl-5-(3
methylbut-2-en-1-yl)pyrrolidin-2-one
5 mol% K 0 0 5 mol% NaBArF4 O4 DCM, 40 °C NH 'N N
[613]
PLUS International IP Law Firm Our ref. PCT2018-151
0
NH
[614] Prepared with Catalyst K (5.9 mg, 5
mol%) and NaBArF 4 (8.8 mg, 5 mol%) . Colorless oil (15mg,
%); 1H NMR spectroscopic analysis of the unpurified
reaction mixture indicated 3.4:1 dr; major isomer (anti
diastereomer); 1H NMR (400 MHz, CDCl,) 5 5.68 (s, 1H), 5.08
(t, J = 7.9 Hz, 1H), 3.18 (dt, J = 8.3, 5.7 Hz, 1H), 2.51
(dd, J = 16.6, 8.3 Hz, 1H), 2.30-2.18 (m, 1H), 2.17-2.07 (m,
2H), 1.99 (dt, J = 16.5, 8.0 Hz, 1H), 1.71 (s, 3H), 1.62 (s,
3H), 1.12 (d, J = 6.7 Hz, 3H); 13C NMR (150 MHz, CDCl3) 5
176.9, 135.4, 119.4, 61.9, 38.8, 35.4, 33.8, 25.8, 18.9,
18.0; IR (cm-1) 3213, 2961, 2923, 1686, 1376; HRMS (EI) m/z
calcd. for CioH17NO [M]+: 167.1310, found: 167.1312.
[615] [Example 62] Preparation of (3S,3aS,5aS,9bR)-3,5a,9
Trimethyl-1,3a,4,5,5a,9b-hexahydro-2H-benzo[g]indole
2, 8 (3H) -dione
Hb 10 mol% K 10 mol% NaBArF 4
0 -CHC1, 40 °C H Ha 0 Allylic No HN 0
[616] 0
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0. HN 0
[617] Prepared with Catalyst K (11.8 mg, mol%), NaBArF4(17.7 mg, 10 mol%), and chloroform (2.4
mL) as a solvent. White solid (21 mg, 43%); 1H NMR
spectroscopic analysis of the unpurified reaction mixture
indicated >20:1 dr; m.p. 299-301°C; 'H NMR (600 MHz, CDCl3)
6.73 (d, J = 9.8 Hz, 1H), 6.24 (d, J = 9.8 Hz, 1H), 5.50
(s, 1H), 4.90 (d, J = 5.5 Hz, 1H), 2.32-2.25 (m, 1H), 2.14
2.07 (m, 1H), 2.02 (s, 3H), 1.84-1.79 (m, 2H), 1.78-1.70 (m,
1H), 1.49-1.38 (m, 1H), 1.33 (s, 3H), 1.30 (d, J = 7.5 Hz,
3 3H); 1 C NMR (150 MHz, CDCl 3 ) 5 186.1, 180.8, 157.6, 151.6,
135.9, 125.9, 52.8, 44.9, 43.6, 39.6, 34.8, 25.7, 23.6,
15.0, 11.2; IR (cm-1) 3181, 2948, 1696, 1651, 1624, 1271,
853, 769; HRMS (EI) m/z calcd. for C1 5 H1 9 NO 2 [M]+: 245.1416,
found: 245.1417.
[618] As seen from Examples 59 to 62, it was found that the
method of preparing a gamma-lactam compound from a
dioxazol-one compound which was an intentionally selected
starting material, using the metal complex of the present
invention as a catalyst may be very useful in preparation
of an intermediate and a raw material of synthesis of
medicines, natural materials, and the like.

Claims (21)

  1. PLUS International IP Law Firm Our ref. PCT2018-151
    [CLAIMS]
    [Claim 1] A metal complex represented by the following Chemical Formula 1:
    [Chemical Formula 1]
    L
    N-'M X
    N A-Ry
    (Re)n
    wherein M is iridium, rhodium, ruthenium, or cobalt;
    R3
    L is R R2 or
    X is a halogen;
    Ri to R5 are independently of one another hydrogen or (Cl-C20)alkyl; and R 6 is a halogen, (Cl-C20)alkyl, halo(Cl C20)alkyl, (Cl-C20)alkoxy, (C6-C20)aryl, or (C3-C20)heteroaryl; A is -CO- or -SO 2 -; R7 is (Cl-C20)alkyl, (Cl-C20)alkoxy,
    PLUS International IP Law Firm Our ref. PCT2018-151
    (C6-C20)aryl, (Cl-C20)alkyl(C6-C20)aryl, or -NRiiRi2;
    Rii and R1 2 are independently of each other hydrogen or (Cl-C20)alkyl; and n is an integer of 0 to 6.
  2. [Claim 2] The metal complex of claim 1, wherein in
    R3
    R4 R2
    Chemical Formula 1, L is R5 -R1 X is Cl
    or Br; Ri to R5 are independently of one
    another (Cl-C20)alkyl; R6 is halo(Cl C20)alkyl or (Cl-C20)alkoxy; and n is an integer of 0 to 6.
  3. [Claim 3] The metal complex of claim 1, wherein Chemical Formula 1 is represented by the following Chemical Formula 2:
    [Chemical Formula 2]
    PLUS International IP Law Firm Our ref. PCT2018-151
    CH 3 H 3C CH 3
    H3C CH 3
    -N
    A-Ry
    (R6)n
    wherein X is a halogen; R6 is halo(Cl-C20)alkyl or (Cl C20)alkoxy; A is -CO- or -SO 2 -; R7 is (Cl-C20)alkyl, (Cl-C20)alkoxy, (C6-C20)aryl, (Cl-C20)alkyl(C6-C20)aryl, or -NR1 1 R 1 2 ;
    Rii and R12 are independently of each
    other hydrogen or (Cl-C20)alkyl; and n is an integer of 0 or 1.
  4. [Claim 4] The metal complex of claim 3, wherein A is -CO-, R6 and R7 are independently of each other (Cl-C20)alkoxy, and n is an integer of 1.
  5. [Claim 5] The metal complex of claim 1, wherein
    PLUS International IP Law Firm Our ref. PCT2018-151
    the metal complex is used as a catalyst for preparing a gamma-lactam compound from a dioxazol-one compound.
  6. [Claim 6] A method of preparing a metal complex represented by the following Chemical Formula 1, the method comprising: reacting a metal precursor compound of the following Chemical Formula 3A and a quinoline-based compound of the following Chemical Formula 3B in the presence of a base to prepare the metal complex of the following Chemical Formula 1:
    [Chemical Formula 1]
    L
    N-'M X
    N A-Ry
    (Re)n
    [Chemical Formula 3A]
    L X-M-X x M-x L
    [Chemical Formula 3B]
    PLUS International IP Law Firm Our ref. PCT2018-151
    (R), N HN 'A-R 7
    wherein M is iridium, rhodium, ruthenium, or cobalt;
    R3
    L is or
    X is independently of each other a halogen;
    Ri to R5 are independently of one
    another hydrogen or (Cl-C20)alkyl; and R 6 is a halogen, (Cl-C20)alkyl, halo(Cl C20)alkyl, (Cl-C20)alkoxy, (C6-C20)aryl, or (C3-C20)heteroaryl; A is -CO- or -SO 2 -; R7 is (Cl-C20)alkyl, (Cl-C20)alkoxy, (C6-C20)aryl, (Cl-C20)alkyl(C6-C20)aryl, or -NR 1 1 R 12 ;
    R 11 and R1 2 are independently of each
    other hydrogen or (Cl-C20)alkyl; and n is an integer of 0 to 6.
  7. [Claim 7]
    PLUS International IP Law Firm Our ref. PCT2018-151
    The method of preparing a metal complex of claim 6, wherein the base is any one or two or more selected from NaOAc, Na 2 CO 3
    , NaHNO 3 , Cu(OAc) 2, Cu(OAc) 2 .H 2 0, and NEt 3
    .
  8. [Claim 8] The method of preparing a metal complex of claim 6, wherein the base is used at 2 to mol with respect to 1 mol of the metal precursor compound of Chemical Formula 3A, and the quinoline-based compound of Chemical Formula 3B is used at 1.5 to 2.5 mol with respect to 1 mol of the metal precursor compound of Chemical Formula 3A.
  9. [Claim 9] A method of preparing a gamma-lactam compound, the method comprising: amidating a dioxazol-one compound in the presence of a metal complex represented by the following Chemical Formula 1 and a base to prepare the gamma-lactam compound:
    [Chemical Formula 1]
    PLUS International IP Law Firm Our ref. PCT2018-151
    L
    - N\ N A-Ry
    (R)n
    wherein M is iridium, rhodium, ruthenium, or cobalt;
    R3
    L is R R2 or
    X is a halogen;
    Ri to R5 are independently of one another hydrogen or (Cl-C20)alkyl; and R 6 is a halogen, (Cl-C20)alkyl, halo(Cl C20)alkyl, (Cl-C20)alkoxy, (C6-C20)aryl, or (C3-C20)heteroaryl; A is -CO- or -SO 2 -; R7 is (Cl-C20)alkyl, (Cl-C20)alkoxy, (C6-C20)aryl, (Cl-C20)alkyl(C6-C20)aryl, or -NR 1 1 R 12 ;
    R 11 and R1 2 are independently of each
    other hydrogen or (Cl-C20)alkyl; and n is an integer of 0 to 6.
    PLUS International IP Law Firm Our ref. PCT2018-151
  10. [Claim 10] The method of preparing a gamma-lactam compound of claim 9, wherein the dioxazol one compound is represented by the following Chemical Formula 4 and the gamma-lactam compound is represented by the following Chemical Formula 5:
    [Chemical Formula 4]
    0 Ra3
    Ra5 R N Ra 4 Ra2
    [Chemical Formula 5]
    Rai0 Ra 2 1 NH Ra3R Ra6 Ra5
    wherein Rai to Ra6 are independently of one another hydrogen, (Cl-C20)alkyl, (C3 C20)cycloalkyl, (C2-C20)alkenyl, (C2 C20)alkynyl, (Cl-C20)alkoxy, (C6-C20)aryl, (C3-C20)heteroaryl, or (C3 C20)heterocycloalkyl, or may be connected to an adjacent substituent to form an aromatic
    PLUS International IP Law Firm Our ref. PCT2018-151
    ring, an alicyclic ring, or spiro ring with or without a fused ring; the alkyl, the cycloalkyl, the alkenyl, the alkynyl, the alkoxy, the aryl, the heteroaryl, the aromatic ring, the alicyclic ring, or the spiro ring of Rai to Ra6 may be
    further substituted by any one or more substituents selected from a halogen, nitro, cyano, (C1-C20)alkyl, (C1-C20)alkenyl, (Cl C20)alkoxy, (C6-C20)aryl, (C6-C20)aryl(C1 C20)alkyl, (C3-C20)heteroaryl, (C3 C20) heterocycloalkyl, and -N (Raii) (Rai2 ) ; and
    Raii and Rai2 are independently of each other hydrogen, (C1-C20)alkyl, or (Cl C20)alkoxycarbonyl.
  11. [Claim 11] The method of preparing a gamma-lactam compound of claim 9, wherein the metal complex is used at 0.01 to 0.1 mol with respect to 1 mol of the dioxazol-one compound.
  12. [Claim 12] The method of preparing a gamma-lactam compound of claim 9, wherein the base is one or two or more selected from NaBArF 4 (sodium
    PLUS International IP Law Firm Our ref. PCT2018-151
    tetrakis [3, 5 bis(trifluoromethyl)phenyl]borate), AgSbF 6 (silver hexafluoroantimonate(V)), AgNTf 2 (silver bis(trifluoromethanesulfonyl)imide), AgBF 4 (silver tetrafluoroborate), AgPF 6 (silver hexafluorophosphate), AgOTf (silver trifluoromethanesulfonate), and AgOAc (silver acetate).
  13. [Claim 13] The method of preparing a gamma-lactam compound of claim 9, wherein the base is used at 0.01 to 0.1 mol with respect to 1 mol of the dioxazol-one compound.
  14. [Claim 14] The method of preparing a gamma-lactam compound of claim 9, wherein the amidating is performed at 20 to 60°C.
  15. [Claim 15] The method of preparing a gamma-lactam compound of claim 9, wherein in Chemical
    R3
    R4 R2
    Formula 1, M is iridium; L is R5 ; X
    is chloro; R1 to R5 are independently of one
    PLUS International IP Law Firm Our ref. PCT2018-151
    another (C1-C20)alkyl; R 6 is (C1-C20)alkoxy;
    A is -CO-; R7 is (C1-C20)alkoxy; and n is an
    integer of 0 or 1.
  16. [Claim 16] The method of preparing a gamma-lactam
    compound of claim 10, wherein
    Rai to Ra5 are independently of each
    other hydrogen, (C1-C20)alkyl, or (C3
    C20)heterocycloalkyl;
    Ra 6 is independently of each other
    hydrogen, (C1-C20)alkyl, (C3-C20)cycloalkyl, (C2-C20)alkenyl, (C2-C20)alkynyl, (C6 C20)aryl, or (C3-C20)heteroaryl, or Ra 5 and
    Ra 6 may be connected to form a (C5-C8)spiro
    ring,
    Ra2 and Ra3 may be connected by (C2
    C10)alkenylene to form a (C6-C12)aromatic
    ring, and in this case, Rai and Ra2 are not
    present,
    Ra3 and Ra6 may be connected to each
    other to form a (C3-C20)alicyclic ring with
    or without an aromatic ring,
    Ra3 and Ra4 and Ra6 may be connected to
    each other to form a (C3-C20)alicyclic ring
    with or without an aromatic ring,
    PLUS International IP Law Firm Our ref. PCT2018-151
    the alkyl Of Rai to Ra5 , and the alkyl, the cycloalkyl, the alkenyl, the alkynyl, the aryl, or the heteroaryl Of Ra6 may be
    further substituted by any one or more
    substituents selected from a halogen, nitro,
    cyano, (C1-C20)alkyl, (C1-C20)alkenyl, (Cl
    C20)alkoxy, (C6-C20)aryl, (C6-C20)aryl(C1
    C20)alkyl, (C3-C20)heterocycloalkyl, and
    N (Raii) (Rai2 ) ; and
    Raii and Rai2 are independently of each
    other hydrogen, (C1-C20)alkyl, or (Cl
    C20)alkoxycarbonyl.
  17. [Claim 17] The method of preparing a gamma-lactam
    compound of claim 9, wherein amidating a
    dioxazol-one compound of the following
    Chemical Formula 6 in the presence of the
    compound represented by Chemical Formula 1
    and the base to prepare a gamma-lactam
    compound of the following Chemical Formula 7
    is included:
    [Chemical Formula 6]
    PLUS International IP Law Firm Our ref. PCT2018-151
    0 Ra3
    Ras N Ra6 Ra2
    [Chemical Formula 7]
    Rai0
    NH Ra3' Ra6 Ra5
    wherein Rai and Ra3 are independently of each other hydrogen, (Cl-C20)alkyl, or (C3 C20)heterocycloalkyl; Ra2 and Ra5 are independently of each other hydrogen or (Cl-C20)alkyl; Ra6 is (Cl-C20)alkyl, (C3 C20)cycloalkyl, (C2-C20)alkenyl, (C2 C20)alkynyl, (C6-C20)aryl, or (C3 C20)heteroaryl; the alkyl, the cycloalkyl, the alkenyl, the alkynyl, the aryl, and the heteroaryl of Ra6 may be further substituted by any one or more substituents selected from a halogen, nitro, cyano, (Cl-C20)alkyl, (C2 C20)alkenyl, (Cl-C20)alkoxy, (C6-C20)aryl,
    PLUS International IP Law Firm Our ref. PCT2018-151
    (C6-C20) aryl (Cl-C20) alkyl, and -N (Raii) (Ra1 2
    ) and Raii and Ral2 are independently of each other hydrogen, (Cl-C20)alkyl, or (Cl C20)alkoxycarbonyl.
  18. [Claim 18] The method of preparing a gamma-lactam compound of claim 9, wherein amidating a dioxazol-one compound of the following Chemical Formula 8 in the presence of the compound represented by Chemical Formula 1 and the base to prepare a gamma-lactam compound of the following Chemical Formula 9 is included:
    [Chemical Formula 8]
    0
    A N0P
    Ra 5 R a1
    [Chemical Formula 9]
    Ra1 0
    Ra 3 NH A Ra 5
    wherein
    PLUS International IP Law Firm Our ref. PCT2018-151
    ring A is a (C3-C20)alicyclic ring with or without an aromatic ring;
    Rai and Ra 3 are independently of one
    another hydrogen or (C1-C20)alkyl;
    Ra 5 is hydrogen or (C2-C20)alkenyl;
    the alkyl of Rai and Ra3 and the alkenyl
    of Ra5 may be further substituted by any one
    or more substituents selected from a
    halogen, nitro, cyano, (C1-C20)alkyl, (C2
    C20)alkenyl, (C1-C20)alkoxy, (C6-C20)aryl,
    (C6-C20)heteroaryl, (C3
    C20) heterocycloalkyl, and -N (Ra 2 1) (Ra 2 2 ) ; and
    Ra21 and Ra22 are independently of each other hydrogen, (C1-C20)alkyl, or (Cl
    C20)alkoxycarbonyl.
  19. [Claim 19] The method of preparing a gamma-lactam
    compound of claim 9, wherein amidating a
    dioxazol-one compound of the following
    Chemical Formula 10 in the presence of the
    compound represented by Chemical Formula 1
    and the base to prepare a gamma-lactam
    compound of the following Chemical Formula
    11 is included:
    [Chemical Formula 10]
    PLUS International IP Law Firm Our ref. PCT2018-151
    0 Ra3 Rai )0 BN
    Ra2
    [Chemical Formula 11]
    Rai 0 Ra 2 Ra 3 NH B
    wherein Rai to Ra3 are independently of one another hydrogen or (Cl-C20)alkyl; ring B is an alicyclic ring; and the alkyl of Rai to Ra 3 and the alicyclic ring of ring B may be further substituted by any one or more substituents selected from a halogen, nitro, cyano, (Cl-C20)alkyl, (C2 C20)alkenyl, (Cl-C20)alkoxy, (C6-C20)aryl, and (C6-C20)aryl(Cl-C20)alkyl.
  20. [Claim 20] The method of preparing a gamma-lactam compound of claim 9, wherein amidating a dioxazol-one compound of the following Chemical Formula 12 in the presence of the compound represented by Chemical Formula 1
    PLUS International IP Law Firm Our ref. PCT2018-151
    and the base to prepare a gamma-lactam compound of the following Chemical Formula 13 is included:
    [Chemical Formula 12]
    0 o-j N Ra6
    Ra 5
    [Chemical Formula 13]
    0
    |1 NH Rae Ra5
    wherein Ra5 and Ra6 are independently of each other hydrogen, (Cl-C20)alkyl, or (C6 C20)aryl.
  21. [Claim 21] A gamma-lactam compound represented by the following Chemical Formula 5:
    [Chemical Formula 5]
    PLUS International IP Law Firm Our ref. PCT2018-151
    Ra1 0 Ra2 NH Ra3 Ra6 Ra4 as
    wherein Rai to Ra6 are independently of one another hydrogen, (Cl-C20)alkyl, (C3 C20)cycloalkyl, (C2-C20)alkenyl, (C2 C20)alkynyl, (Cl-C20)alkoxy, (C6-C20)aryl, (C3-C20)heteroaryl, or (C3 C20)heterocycloalkyl, or may be connected to an adjacent substituent to form an aromatic ring, an alicyclic ring, or spiro ring with or without a fused ring; the alkyl, the cycloalkyl, the alkenyl, the alkynyl, the alkoxy, the aryl, the heteroaryl, the aromatic ring, the alicyclic ring, or the spiro ring of Rai to Ra6 may be further substituted by any one or more substituents selected from a halogen, nitro, cyano, (Cl-C20)alkyl, (Cl-C20)alkenyl, (Cl C20)alkoxy, (C6-C20)aryl, (C6-C20)aryl(Cl C20)alkyl, (C3-C20)heteroaryl, (C3 C20)heterocycloalkyl, and -N(Raii) (Ra12); and Raii and Ral2 are independently of each
    PLUS International IP Law Firm Our ref. PCT2018-151
    other hydrogen, (C1-C20)alkyl, or (Cl C20)alkoxycarbonyl.
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